Cannabinoid receptor ligands and uses thereof

ABSTRACT

Compounds of Formula (I) and (II) that act as cannabinoid receptor ligands and their uses in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals are described herein.

This application claims the benefit of U.S. Provisional Application No.60/464,831 filed on Apr. 23, 2003 and incorporated herein by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to bicyclic pyrazolyl and imidazolylcompounds as cannabinoid receptor ligands, in particular CB1 receptorantagonists, and uses thereof for treating diseases, conditions and/ordisorders modulated by cannabinoid receptor antagonists.

BACKGROUND

Obesity is a major public health concern because of its increasingprevalence and associated health risks. Obesity and overweight aregenerally defined by body mass index (BMI), which is correlated withtotal body fat and estimates the relative risk of disease. BMI iscalculated by weight in kilograms divided by height in meters squared(kg/m²). Overweight is typically defined as a BMI of 25-29.9 kg/m², andobesity is typically defined as a BMI of 30 kg/m². See, e.g., NationalHeart, Lung, and Blood Institute, Clinical Guidelines on theIdentification, Evaluation, and Treatment of Overweight and Obesity inAdults, The Evidence Report, Washington, D.C.: U.S. Department of Healthand Human Services, NIH publication no. 98-4083 (1998).

The increase in obesity is of concern because of the excessive healthrisks associated with obesity, including coronary heart disease,strokes, hypertension, type 2 diabetes mellitus, dyslipidemia, sleepapnea, osteoarthritis, gall bladder disease, depression, and certainforms of cancer (e.g., endometrial, breast, prostate, and colon). Thenegative health consequences of obesity make it the second leading causeof preventable death in the United States and impart a significanteconomic and psychosocial effect on society. See, McGinnis M, Foege WH., “Actual Causes of Death in the United States,” JAMA, 270, 2207-12(1993).

Obesity is now recognized as a chronic disease that requires treatmentto reduce its associated health risks. Although weight loss is animportant treatment outcome, one of the main goals of obesity managementis to improve cardiovascular and metabolic values to reduceobesity-related morbidity and mortality. It has been shown that 5-10%loss of body weight can substantially improve metabolic values, such asblood glucose, blood pressure, and lipid concentrations. Hence, it isbelieved that a 5-10% intentional reduction in body weight may reducemorbidity and mortality.

Currently available prescription drugs for managing obesity generallyreduce weight by inducing satiety or decreasing dietary fat absorption.Satiety is achieved by increasing synaptic levels of norepinephrine,serotonin, or both. For example, stimulation of serotonin receptorsubtypes 1B, 1D, and 2C and 1- and 2-adrenergic receptors decreases foodintake by regulating satiety. See, Bray G A, “The New Era of DrugTreatment. Pharmacologic Treatment of Obesity: Symposium Overview,” ObesRes., 3 (suppl 4), 415s-7s (1995). Adrenergic agents (e.g.,diethylpropion, benzphetamine, phendimetrazine, mazindol, andphentermine) act by modulating central norepinephrine and dopaminereceptors through the promotion of catecholamine release. Olderadrenergic weight-loss drugs (e.g., amphetamine, methamphetamine, andphenmetrazine), which strongly engage in dopamine pathways, are nolonger recommended because of the risk of their abuse. Fenfluramine anddexfenfluramine, both serotonergic agents used to regulate appetite, areno longer available for use.

More recently, CB1 cannabinoid receptor antagonists/inverse agonistshave been suggested as potential appetite suppressants. See, e.g.,Arnone, M., et al., “Selective Inhibition of Sucrose and Ethanol Intakeby SR141716, an Antagonist of Central Cannabinoid (CB1) Receptors,”Psychopharmacol, 132, 104-106 (1997); Colombo, G., et al., “AppetiteSuppression and Weight Loss after the Cannabinoid Antagonist SR141716,”Life Sci., 63, PL113-PL117 (1998); Simiand, J., et al., “SR141716, a CB1Cannabinoid Receptor Antagonist, Selectively Reduces Sweet Food Intakein Marmose,” Behav. Pharmacol., 9, 179-181 (1998); and Chaperon, F., etal., “Involvement of Central Cannabinoid (CB1) Receptors in theEstablishment of Place Conditioning in Rats,” Psychopharmacology, 135,324-332 (1998). For a review of cannabinoid CB1 and CB2 receptormodulators, see Pertwee, R. G., “Cannabinoid Receptor Ligands: Clinicaland Neuropharmacological Considerations, Relevant to Future DrugDiscovery and Development,” Exp. Opin. Invest. Drugs, 9 (7), 1553-1571(2000).

Although investigations are on-going, there still exists a need for amore effective and safe therapeutic treatment for reducing or preventingweight-gain.

In addition to obesity, there also exists an unmet need for treatment ofalcohol abuse. Alcoholism affects approximately 10.9 million men and 4.4million women in the United States. Approximately 100,000 deaths peryear have been attributed to alcohol abuse or dependence. Health risksassociated with alcoholism include impaired motor control and decisionmaking, cancer, liver disease, birth defects, heart disease, drug/druginteractions, pancreatitis and interpersonal problems. Studies havesuggested that endogenous cannabinoid tone plays a critical role in thecontrol of ethanol intake. The endogenous CB1 receptor antagonistSR-141716A has been shown to block voluntary ethanol intake in rats andmice. See, Arnone, M., et al., “Selective Inhibition of Sucrose andEthanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB1)Receptors,” Psychopharmacol, 132, 104-106 (1997). For a review, seeHungund, B. L and B. S. Basavarajappa, “Are Anadamide and CannabinoidReceptors involved in Ethanol Tolerance? A Review of the Evidence,”Alcohol & Alcoholism. 35 (2) 126-133, 2000.

Current treatments for alcohol abuse or dependence generally suffer fromnon-compliance or potential hepatotoxicity; therefore, there is a highunmet need for more effective treatment of alcohol abuse/dependence.

SUMMARY

The present invention provides compounds of Formula (I) or (II) that actas cannabinoid receptor ligands (in particular, CB1 receptorantagonists)

wherein

A is nitrogen and B is carbon, or A is carbon and B is nitrogen;

R⁰ is an aryl optionally substituted with one or more substituents, or aheteroaryl optionally substituted with one or more substituents(preferably, R⁰ is a substituted phenyl, more preferably a phenylsubstituted with one to three substituents independently selected fromthe group consisting of halo (preferably, chloro or fluoro),(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl (preferablyfluoro-substituted alkyl), and cyano, most preferably, R⁰ is2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl);

R¹ is aryl optionally substituted with one or more substituents,heteroaryl optionally substituted with one or more substituents,—CH═CH—R^(1a), or —CH₂CH₂—R^(1a), where R^(1a) is hydrogen or a chemicalmoiety selected from (C₁-C₈)alkyl, 3- to 8-membered partially or fullysaturated carbocyclic ring(s), 3- to 6-membered partially or fullysaturated heterocycle, aryl, heteroaryl, where the chemical moiety isoptionally substituted with one or more substituents;

X is a bond or —C(R^(2a))(R^(2b)), where R^(2a) and R^(2b) are eachindependently hydrogen, (C₁-C₄)alkyl, or halo-substituted (C₁-C₄)alkyl(preferably, R^(2a) and R^(2b) are both hydrogen);

R^(3a) and R^(3b) are each independently hydrogen, (C₁-C₄)alkyl, orhalo-substituted (C₁-C₄)alkyl; and

R⁴ is a chemical moiety selected from the group consisting of(C₁-C₈)alkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, a 3- to 8-memberedpartially or fully saturated carbocyclic ring(s),heteroaryl(C₁-C₃)alkyl, 5-6 membered lactone, 5- to 6-membered lactam,and a 3- to 8-membered partially or fully saturated heterocycle, wheresaid chemical moiety is optionally substituted with one or moresubstituents;

a pharmaceutically acceptable salt thereof, a prodrug of the compound orthe salt, or a solvate or hydrate of the compound, the salt or theprodrug.

In a preferred embodiment of the present invention, a compound ofFormula (III) or (IV) is provided.

wherein

A, B, X, R^(2a), R^(2b), R^(3a), R^(3b) and R⁴ are as defined above;

R^(0a), R^(0b), R^(1b), and R^(1c) are each independently halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or cyano;

n and m are each independently 0, 1 or 2;

a pharmaceutically acceptable salt thereof, a prodrug of the compound orthe salt, or a solvate or hydrate of the compound, the salt or theprodrug.

In preferred embodiments of the present invention, R⁴ is a chemicalmoiety selected from the group consisting of (C₁-C₈)alkyl,aryl(C₁-C₄)alkyl, and 3- to 8-membered partially or fully saturatedcarbocydic ring(s), where said chemical moiety is optionally substitutedwith one or more substituent.

More preferably, R⁴ is (C₁-C₈)alkyl, halo-substituted (C₁-C₈)alkyl,cyclopentyl, cyclohexyl, piperidin-1-yl, pyrrolidin-1-yl, ormorpholin-1-yl.

Preferably, R⁰ and R¹ are each independently a phenyl substituted with 1to 3 substituents independently selected from the group consisting ofhalo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, andcyano;

More preferably, R⁰ and R¹ are each independently a phenyl substitutedwith 1 to 2 substituents independently selected from the groupconsisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano;

Most preferably, R⁰ is 2-chlorophenyl, 2-fluorophenyl,2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl; and R¹ is 4-chlorophenyl, 4-cyanophenyl or4-fluorophenyl.

Preferred compounds of Formula (I) where A is nitrogen, B is carbon andX is a bond include:2-(2-chloro-phenyl)-5-isopropyl-3-(3,4,5-trifluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2,3-bis-(2-chloro-phenyl)-5-isopropyl4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-5-isopropyl-3-(4-methoxymethyl-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-(2-fluoro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-5-isopropyl-3-(6-methoxy-pyridin-3-yl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(3-chloro-4-fluoro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-(4-fluoro-3-methyl-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4-methyl4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;4-benzyl-3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;5-tert-butyl-3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-cyclobutyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-cyclopentyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-cyclohexyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;5-tert-butyl-3-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-5-cyclopentyl-2-(2,4-dichloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(2-chloro-phenyl)-2-(4-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(2-chloro-phenyl)2-(4-chloro-phenyl)-5-cyclopentyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(2-chloro-phenyl)2-(4-chloro-phenyl)-5-cyclohexyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;5-bicyclo[2.2.1]hept-2-yl-3-(2-chloro-phenyl-2-(4-chloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(4-chloro-phenyl)-5-cyclopentyl-3-(2-fluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol6-one;and 2-(4-chloro-phenyl)-5-cyclohexyl-3-(2-fluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.

More preferred compounds include:3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;and4-[2-(2-Chloro-phenyl)-5-isopropyl-6-oxo-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzonitrile;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

Preferred compounds of Formula (I) where A is nitrogen, B is carbon andX is —C(R^(2a))R^(2b))— include:3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-6-isopropyl-2,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-6-(2,2,2-trifluoro-ethyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-6-(2,2-difluoro-ethyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;and3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-6-(2-fluoro-ethyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

Preferred compounds of Formula (I) where A is carbon, B is nitrogen andX is a bond include:2-(4-chloro-phenyl)-5-cyclopentyl-1-(2-fluoro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-5-cyclopentyl-1-(2,4-dichloro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-5-cyclohexyl-1-(2,4-dichloro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-cyclopentyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-cyclohexyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(2-chloro-phenyl)-1-(4chloro-phenyl)-5-cyclohexyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(4-chloro-phenyl)-5-cyclohexylmethyl-1-(2-fluoro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;5-cyclopentyl-2-(4-fluoro-phenyl)-1-(2-fluoro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;1-(2-chloro-phenyl)-5-cyclopentyl-2-(4-fluoro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(2-chloro-phenyl)-1-(4-chloro-phenyl)-5-cyclopentyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;2-(2-chloro-phenyl)-1-(4-chloro-phenyl)-5-cyclohexyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;and1-(4-chloro-phenyl)-5-cyclohexyl-2-(2,4-dichloro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

A more preferred compound is2-(4-chloro-phenyl)-5-cyclopentyl-1-(2-fluoro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

A preferred compound of Formula (I) where A is carbon, B is nitrogen andX is —C(R^(2a))R^(2b))— is2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-cyclopentyl-1,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-4-one;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

Preferred compounds of Formula (I) where R¹ is —CH═CH—R^(1a) include:2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-5-isopropyl-3-vinyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-(2,2,2-trifluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-(2,2-difluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;and2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-(2-fluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

Preferred compounds of Formula (II) include:2-(4-chloro-phenyl)-5-cyclohexyl-3-(2-fluoro-phenyl)-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole;3-(4-chloro-phenyl)-5-cyclopentyl-2-2,4-dichloro-phenyl)-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole;and3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofthe compound or the salt.

Some of the compounds described herein may contain at least one chiralcenter; consequently, those skilled in the art will appreciate that allstereoisomers (e.g., enantiomers and diasteroisomers) of the compoundsillustrated and discussed herein are within the scope of the presentinvention. In addition, tautomeric forms of the compounds are alsowithin the scope of the present invention. Those skilled in the art willrecognize that chemical moieties such as an alpha-amino ether or analpha-chloro amine may be too unstable to isolate; therefore, suchmoieties do not form a part of this invention.

Compounds of the present invention have been shown to be usefulcannabinoid receptor ligands (in particular, CB1 receptor antagonists).Accordingly, another aspect of the present invention is a pharmaceuticalcomposition that comprises (1) a compound of the present invention, and(2) a pharmaceutically acceptable excipient, diluent, or carrier.Preferably, the composition comprises a therapeutically effective amountof a compound of the present invention. The composition may also containat least one additional pharmaceutical agent (described herein).Preferred agents include nicotine receptor partial agonists, opioidantagonists (e.g., naltrexone and nalmefene), dopaminergic agents (e.g.,apomorphine), attention deficit disorder (ADD including attentiondeficit hyperactivity disorder (ADHD)) agents (e.g., Ritalin™,Strattera™, Concerta™ and Adderall™), and anti-obesity agents (describedherein below).

In yet another embodiment of the present invention, a method fortreating a disease, condition or disorder modulated by a cannabinoidreceptor (preferably, a CB1 receptor) antagonists in animals thatincludes the step of administering to an animal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention (or a pharmaceutical composition thereof.

Diseases, conditions, and/or disorders modulated by cannabinoid receptorantagonists include eating disorders (e.g., binge eating disorder,anorexia, and bulimia), weight loss or control (e.g., reduction incalorie or food intake, and/or appetite suppression), obesity,depression, atypical depression, bipolar disorders, psychoses,schizophrenia, behavioral addictions, suppression of reward-relatedbehaviors (e.g., conditioned place avoidance, such as suppression ofcocaine- and morphine-induced conditioned place preference), substanceabuse, addictive disorders, impulsivity, alcoholism (e.g., alcoholabuse, addiction and/or dependence including treatment for abstinence,craving reduction and relapse prevention of alcohol intake), tobaccoabuse (e.g., smoking addiction, cessation and/or dependence includingtreatment for craving reduction and relapse prevention of tobaccosmoking), dementia (including memory loss, Alzheimer's disease, dementiaof aging, vascular dementia, mild cognitive impairment, age-relatedcognitive decline, and mild neurocognitive disorder), sexual dysfunctionin males (e.g., erectile difficulty), seizure disorders, epilepsy,inflammation, gastrointestinal disorders (e.g., dysfunction ofgastrointestinal motility or intestinal propulsion), attention deficitdisorder (ADD/ADHD), Parkinson's disease, and type II diabetes. In apreferred embodiment, the method is used in the treatment of weightloss, obesity, bulimia, ADD/ADHD, Parkinson's disease, dementia,alcoholism, and/or tobacco abuse.

Compounds of the present invention may be administered in combinationwith other pharmaceutical agents. Preferred pharmaceutical agentsinclude nicotine receptor partial agonists, opioid antagonists (e.g.,naltrexone (including naltrexone depot), antabuse, and nalmefene),dopaminergic agents (e.g., apomorphine), ADD/ADHD agents (e.g.,methylphenidate hydrochloride (e.g., Ritalin™ and Concerta™),atomoxetine (e.g., Strattera™), and amphetamines (e.g., Adderall™)) andanti-obesity agents, such as apo-B/MTP inhibitors, 11β-hydroxy steroiddehydrogenase-1 (11β-HSD type 1) inhibitors, peptide YY₃₋₃₆ or analogsthereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors,sympathomimetic agents, β₃ adrenergic receptor agonists, dopaminereceptor agonists, melanocyte-stimulating hormone receptor analogs,5-HT2c receptor agonists, melanin concentrating hormone receptorantagonists, leptin, leptin analogs, leptin receptor agonists, galaninreceptor antagonists, lipase inhibitors, bombesin receptor agonists,neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonistssuch as those described herein below), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andthe like.

The combination therapy may be administered as (a) a singlepharmaceutical composition which comprises a compound of the presentinvention, at least one additional pharmaceutical agent described hereinand a pharmaceutically acceptable excipient, diluent, or carrier; or (b)two separate pharmaceutical compositions comprising (i) a firstcomposition comprising a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent described herein and a pharmaceutically acceptable excipient,diluent, or carrier. The pharmaceutical compositions may be administeredsimultaneously or sequentially and in any order.

In yet another aspect of the present invention, a pharmaceutical kit isprovided for use by a consumer to treat diseases, conditions ordisorders modulated by cannabinoid receptor antagonists in an animal.The kit comprises a) a suitable dosage form comprising a compound of thepresent invention; and b) instructions describing a method of using thedosage form to treat diseases, conditions or disorders that aremodulated by cannabinoid receptor (in particular, the CB1 receptor)antagonists.

In yet another embodiment of the present invention is a pharmaceuticalkit comprising: a) a first dosage form comprising (i) a compound of thepresent invention and (ii) a pharmaceutically acceptable carrier,excipient or diluent; b) a second dosage form comprising (i) anadditional pharmaceutical agent described herein, and (ii) apharmaceutically acceptable carrier, excipient or diluent; and c) acontainer.

Definitions

As used herein, the term “alkyl” refers to a hydrocarbon radical of thegeneral formula C_(n)H_(2n+1). The alkane radical may be straight orbranched. For example, the term “(C₁-C₆)alkyl” refers to a monovalent,straight, or branched aliphatic group containing 1 to 6 carbon atoms(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl(e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio group have thesame definition as above. When indicated as being “optionallysubstituted”, the alkane radical or alkyl moiety may be unsubstituted orsubstituted with one or more substituents (generally, one to threesubsbtuents except in the case of halogen substituents such as perchloroor perfluoroalkyls) independently selected from the group ofsubstituents listed below in the definition for “substituted.”“Halo-substituted alkyl” refers to an alkyl group substituted with oneor more halogen atoms (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, perfluoroethyl, and the like). When substituted, thealkane radicals or alkyl moieties are preferably substituted with 1 to 3fluoro substituents, or 1 or 2 substituents independently selected from(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to6-membered heterocycle, chloro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy,amino, (C₁-C₆)alkyl amino, di-(C₁-C₄)alkyl amino, aminocarboxylate(i.e., (C₁-C₃)alkyl-O—C(O)—NH—), hydroxy(C₂-C₃)alkylamino, or keto(oxo), and more preferably, 1 to 3 fluoro groups, or 1 substituentselected from (C₁-C₃)alkyl, (C₃-C₆)cydoalkyl, (C₆)aryl,6-membered-heteroaryl, 3- to 6-membered heterocycle, (C₁-C₃)alkoxy,(C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino.

The terms “partially or fully saturated carbocyclic ring” (also referredto as “partially or fully saturated cycloalkyl”) refers to nonaromaticrings that are either partially or fully hydrogenated and may exist as asingle ring, bicydic ring or a spiral ring. Unless specified otherwise,the carbocyclic ring is generally a 3- to 8-membered ring. For example,partially or fully saturated carbocyclic rings (or cycloalkyl) includegroups such as cydopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbornyl,bicyclo[2.2.2]octyt, and the like. When designated as being “optionallysubstituted”, the partially saturated or fully saturated cycloalkylgroup may be unsubstituted or substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted.”A substituted carbocydic ring also includes groups wherein thecarbocyclic ring is fused to a phenyl ring (e.g., indanyl). Thecarbocyclic group may be attached to the chemical entity or moiety byany one of the carbon atoms within the carbocydic ring system. Whensubstituted, the carbocyclic group is preferably substituted with 1 or 2substituents independently selected from (C₁-C₃)alkyl, (C₂-C₃)alkenyl,(C₁-C₆)alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle,chloro, fluoro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy, amino,(C₁-C₆)alkyl amino, di-(C₁-C₄)alkyl amino, aminocarboxylate (i.e.,(C₁-C₃)alkyl-O—C(O)—NH—), hydroxy(C₂-C₃)alkylamino, or keto (oxo), andmore preferably 1 or 2 from substituents independently selected from(C₁-C₂)alkyl, 3- to 6-membered heterocycle, fluoro, (C₁-C₃)alkoxy,(C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. Similarly, any cycloalkylportion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) hasthe same definition as above.

The term “partially saturated or fully saturated heterocyclic ring”(also referred to as “partially saturated or fully saturatedheterocycle”) refers to nonaromatic rings that are either partially orfully hydrogenated and may exist as a single ring, bicyclic ring or aspiral ring. Unless specified otherwise, the heterocyclic ring isgenerally a 3- to 6-membered ring containing 1 to 3 heteroatoms(preferably 1 or 2 heteroatoms) independently selected from sulfur,oxygen and/or nitrogen. Partially saturated or fully saturatedheterocyclic rings include groups such as epoxy, aziridinyl,tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl,N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl,piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl,oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, and the like. When indicated as being“optionally substituted”, the partially saturated or fully saturatedheterocycle group may be unsubstiuted or substituted with one or moresubstituents (typically, one to three substituents) independentlyselected from the group of substituents listed below in the definitionfor “substituted.” A substituted heterocyclic ring includes groupswherein the heterocyclic ring is fused to an aryl or heteroaryl ring(e.g., 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl,2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, etc.). Whensubstituted, the heterocycle group is preferably substituted with 1 or 2substituents independently selected from (C₁-C₃)alkyl, (C₃-C₆)cydoalkyl,(C₂-C₄)alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro,fluoro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₃)alkyl amino, aminocarboxylate (i.e.,(C₁-C₃)alkyl-O—C(O)—NH—), or keto (oxo), and more preferably with 1 or 2substituents independently selected from (C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₆)aryl, 6-membered-heteroaryl, 3- to 6-memberedheterocycle, or fluoro. The heterocyclic group may be attached to thechemical entity or moiety by any one of the ring atoms within theheterocyclic ring system. Similarly, any heterocycle portion of a group(e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.) hasthe same definition as above.

The term “aryl” or “aromatic carbocyclic ring” refers to aromaticmoieties having a single (e.g., phenyl) or a fused ring system (e.g.,naphthalene, anthracene, phenanthrene, etc.). A typical aryl group is a6- to 10-membered aromatic carbocyclic ring(s). When indicated as being“optionally substituted”, the aryl groups may be unsubstituted orsubstituted with one or more substituents (preferably no more than threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” Substituted arylgroups include a chain of aromatic moieties (e.g., biphenyl, terphenyl,phenylnaphthalyl, etc.). When substituted, the aromatic moieties arepreferably substituted with 1 or 2 substituents independently selectedfrom (C₁-C₄)alkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to 6-memberedheterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C₁-C₄)alkoxy,aryloxy, amino, (C₁-C₆)alkyl amino, di-(C₁-C₃)alkyl amino, oraminocarboxylate (i.e., (C₁-C₃)alkyl-O—C(O)—NH—), and more preferably, 1or 2 substituents independently selected from (C₁-C₄)alkyl, chloro,fluoro, cyano, hydroxy, or (C₁-C₄)alkoxy. The aryl group may be attachedto the chemical entity or moiety by any one of the carbon atoms withinthe aromatic ring system. Similarly, the aryl portion (i.e., aromaticmoiety) of an aroyl or aroyloxy (i.e., (aryl)-C(O)—O—) has the samedefinition as above.

The term “heteroaryl” or “heteroaromatic ring” refers to aromaticmoieties containing at least one heteratom (e.g., oxygen, sulfur,nitrogen or combinations thereof) within a 5- to 10-membered aromaticring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl,thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl,triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl,quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, etc.). Theheteroaromatic moiety may consist of a single or fused ring system. Atypical single heteroaryl ring is a 5- to 6-membered ring containing oneto three heteroatoms independently selected from oxygen, sulfur andnitrogen and a typical fused heteroaryl ring system is a 9 to10-membered ring system containing one to four heteroatoms independentlyselected from oxygen, sulfur and nitrogen. When indicated as being“optionally substituted”, the heteroaryl groups may be unsubstituted orsubstituted with one or more substituents (preferably no more than threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” When substituted, theheteroaromatic moieties are preferably substituted with 1 or 2substituents independently selected from (C₁-C₄)alkyl, (C₂-C₃)alkenyl,aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro,iodo, cyano, hydroxy, (C₁-C₄)alkoxy, aryloxy, amino, (C₁-C₆)alkyl amino,di-(C₁-C₃)alkyl amino, or aminocarboxylate (i.e.,(C₁-C₃)alkyl-O—C(O)—NH—), and more preferably, 1 or 2 substituentsindependently selected from (C₁-C₄)alkyl, chloro, fluoro, cyano,hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. Theheteroaryl group may be attached to the chemical entity or moiety by anyone of the atoms within the aromatic ring system (e.g., imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl). Similarly, the heteroarylportion (i.e., heteroaromatic moiety) of a heteroaroyl or heteroaroyloxy(i.e., (heteroaryl)-C(O)—O—) has the same definition as above.

The term “acyl” refers to hydrogen, alkyl, partially saturated or fullysaturated cycloalkyl, partially saturated or fully saturatedheterocycle, aryl, and heteroaryl substituted carbonyl groups. Forexample, acyl includes groups such as (C₁-C₆)alkanoyl (e.g., formyl,acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cydopropylcarbonyl, cydobutylcarbonyl,cyclopentylcarbonyl, cydohexylcarbonyl, etc.), heterocyclic carbonyl(e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl,piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl,etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g.,thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitionsabove. When indicated as being “optionally substituted”, the acyl groupmay be unsubstituted or optionally substituted with one or moresubstituents (typically, one to three substituents) independentlyselected from the group of substituents listed below in the definitionfor “substituted” or the alkyl, cycloalkyl, heterocycle, aryl andheteroaryl portion of the acyl group may be substituted as describedabove in the preferred and more preferred list of substituents,respectively.

The term “substituted” specifically envisions and allows for one or moresubstitutions that are common in the art. However, it is generallyunderstood by those skilled in the art that the substituents should beselected so as to not adversely affect the pharmacologicalcharacteristics of the compound or adversely interfere with the use ofthe medicament. Suitable substituents for any of the groups definedabove include (C₁-C₆)alkyl, (C₃-C₇)cydoalkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, halo(e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C₁-C₆)alkoxy,aryloxy, sulfhydryl (mercapto), (C₁-C₆)alkylthio, arylthio, amino, mono-or di-(C₁-C₆)alkyl amino, quaternary ammonium salts, amino(C₁-C₆)alkoxy,aminocarboxylate (i.e., (C₁-C₆)alkyl-O—C(O)—NH—),hydroxy(C₂-C₆)alkylamino, amino(C₁-C₆)alkylthio, cyanoamino, nitro,(C₁-C₆)carbamyl, keto (oxo), acyl, (C₁-C₆)alkyl-CO₂—, glycolyl, glycyl,hydrazino, guanyl, sufamyl, sulfonyl, sulfinyl, thio(C₁-C₆)alkyl-C(O)—,thio(C₁-C₆)alkyl-CO₂—, and combinations thereof. In the case ofsubstituted combinations, such as “substituted aryl(C₁-C₆)alkyl”, eitherthe aryl or the alkyl group may be substituted, or both the aryl and thealkyl groups may be substituted with one or more substituents(typically, one to three substituents except in the case of perhalosubstitutions). An aryl or heteroaryl substituted carbocyclic orheterocyclic group may be a fused ring (e.g., indanyl,dihydrobenzofuranyl, dihydroindolyl, etc.).

The term “solvate” refers to a molecular complex of a compoundrepresented by Formula (I) or (II) (including prodrugs andpharmaceutically acceptable salts thereof) with one or more solventmolecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water.

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

The term “animal” refers to humans (male or female), companion animals(e.g., dogs, cats and horses), food-source animals, zoo animals, marineanimals, birds and other similar animal species. “Edible animals” refersto food-source animals such as cows, pigs, sheep and poultry.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “treating”, “treat”, or “treatment” embrace both preventative,i.e., prophylactic, and palliative treatment.

The terms “modulated by a cannabinoid receptor” or “modulation of acannabinoid receptor” refers to the activation or deactivation of acannabinoid receptor. For example, a ligand may act as an agonist,partial agonist, inverse agonist, antagonist, or partial antagonist.

The term “antagonist” includes both full antagonists and partialantagonists, as well as inverse agonists.

The term “CB-1 receptor” refers to the G-protein coupled type 1cannabinoid receptor.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formulae (I), (II), (III),and (IV), prodrugs thereof, pharmaceutically acceptable salts of thecompounds, and/or prodrugs, and hydrates or solvates of the compounds,salts, and/or prodrugs, as well as, all stereoisomers (includingdiastereoisomers and enantiomers), tautomers and isotopically labeledcompounds.

As used herein, structures drawn with circles within a ring designatearomatidty. For example, the following chemical moiety designates apyrazole ring when A is a nitrogen and B is a carbon; and the chemicalmoiety designates an imidazole when A is a carbon and B is a nitrogen.

DETAILED DESCRIPTION

The present invention provides compounds and pharmaceutical formulationsthereof that are useful in the treatment of diseases, conditions and/ordisorders modulated by cannabinoid receptor antagonists.

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For a more detailed description of theindividual reaction steps, see the Examples section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the inventive compounds. Although specific starting materialsand reagents are depicted in the schemes and discussed below, otherstarting materials and reagents can be easily substituted to provide avariety of derivatives and/or reaction conditions. In addition, many ofthe compounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will vary depending onthe nature of the remote functionality and the conditions of thepreparation methods. Suitable amino-protecting groups (NH—Pg) includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz)and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protectionis readily determined by one skilled in the art. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

Scheme I outlines the general procedures one could use to providecompounds of the present invention where A is nitrogen, B is carbon, Xis a bond and R^(3a) and R^(3b) are both hydrogen.

The pyrazole intermediate I-1a may be prepared by cyclizing the desiredhydrazine with acetylene dicarboxylate in the presence of a weak base(e.g., alkali metal carbonate, such as potassium carbonate) in a proticsolvent (e.g., ethanol) under refluxing conditions. Intermediate I-1bmay then be produced by treating the pyrazole intermediate I-1a withphosphorus oxybromide in the presence of dimethylformamide (DMF) in anaprotic solvent (e.g., 1,2-dichloroethane) with heat. The amino group(R⁴—NH) may then be introduced into the molecule by treating the formylcompound I-1b with the desired amine (R⁴—NH) in the presence of sodiumtriacetoxy-borohydride and a weak add (e.g., acetic acid). A variety ofsuitable amine compounds are available commercially or easilysynthesized using procedures well documented in the literature. Thelactam may then be formed by hydrolyzing the pendant ester group andcondensing the pendant amino group with the carboxylic acid function toform the amide linkage. The lactam formation may be accomplished usingprocedures well known to those skilled in the art. For example, thecarboxylate ester intermediate I-1c may be hydrolyzed using a strongbase (e.g., alkali metal hydroxide) in a polar solvent (e.g., ethanol)with heat. The amide linkage can then be formed by treating theresulting carboxylic acid with 1-propanephosphoric acid cyclic anhydridein the presence of a non-reactive base (e.g., triethylamine). Finally,the R¹ group is introduced into the molecule by displacing the bromogroup with the desired R¹ group. This may be accomplished by treatingthe bromo intermediate I-1d with either the desired boronic acid(R¹—B(OH)₂) or tin reagent (R¹SnR₃) in the presence of cesium fluorideand tetrakis(triphenylphosphine)palladium(0) in a polar solvent(1,2-dimethoxyethane) at elevated temperatures (e.g., 100° C.).

Alternatively, compounds of the present invention where A is nitrogen, Bis carbon and X is a bond, may be prepared using the procedures outlinedbelow in Scheme II. Scheme II also illustrates the introduction of avinyl moiety at the R¹ position which can be further modified byreducing the olefin functionality.

In Scheme II, the R¹ moiety is introduced earlier in the syntheticscheme. Using the same basic procedures described above for thedisplacement of the bromo group in intermediate I-1d, intermediate I-1bmay be treated with the appropriate boronic add or tin reagent toproduce intermediate I-2a. The desired amine functionality may then beintroduced, followed by hydrolysis to the corresponding carboxylic add,and then cyclization to the lactam using the same general proceduresdiscussed above in Scheme I. When R¹ of Compound I-A is a vinyl group,the compound may be further modified by reacting the vinyl group withthe desired aryl halide (e.g., bromide or iodide) or heteroaryl halide(e.g., bromide or iodide) in the presence of palladium acetate. CompoundI-B may be further modified by reducing the double bond in the pendantgroup (R^(1a)—CH═CH—) of Compound I-B using standard reductionprocedures, such as those described in J. Amer. Chem Soc., 91, 5769(1969). For example, Compound I-B is refluxed in 2-ethoxyethanol in thepresence of p-toluenesulfonylhydrazine.

Scheme III below illustrates the preparation of compounds of the presentinvention where A is a nitrogen, B is carbon and X is—(C(R^(2a))(R^(2b)))—.

An extra methylene is introduced in the molecule by first reactingintermediate I-2a with(2-(trimethylsilyl)ethoxymethyl)triphenyl-phosphonium chloride in thepresence of sodium hydride to form the siloxy intermediate I-3a. Thesiloxy group may then be removed by treating intermediate I-3a with astrong acid (e.g., conc. hydrofluoric acid). The desired aminofunctionality may then be introduced by treating intermediate I-3b withthe appropriate amine (R⁴NH₂) using procedures discussed above (e.g,treatment with sodium triacetoxyborohydride and acetic acid, in1,2-dichloroethane). Cyclization to the lactam may be accomplished byfirst hydrolyzing the ester to the carboxylic acid and then cyclizing tothe lactam using procedures analogous to those discussed above (e.g.,(1) treatment with KOH, EtOH, heat, then acidification; and (2)treatment with 1-propanephosphoric acid cyclic anhydride andtriethylamine in dichloromethane).

Scheme IV provides an alternative route for the synthesis of compoundsof the present invention where A is nitrogen, B is carbon and X is abond.

Starting material I-4a may be prepared using procedures described byBarth, et al., in European Application EP656354. The halo group (e.g.,bromo) may be introduced onto the pendant methyl group using proceduresanalogous to those described by Barth, et al., in PCT applicationWO97/19063. For example, starting material I-4a may be treated with2,2′-azobisisobutyronitrile (AIBN) in carbon tetrachloride at elevatedtemperatures. The bromo group in I-4b may then be displaced with thedesired amino functionality using the same general procedures discussedabove. The compound I-A can be formed by first hydrolyzing the estergroup of I-4c, followed by formation of the amide linkage using thegeneral procedures discussed earlier. Compound I-A may be furthermodified by attaching one or two pendant groups on the carbon adjacentto the lactam nitrogen by treating Compound I-A with the desiredreagents (R^(2a)—L and/or R^(2a)—L, where L is a leaving group, such ahalo group (e.g., bromo)) in the presence of potassiumhexamethyldisilazide (KHMDSi) as described in Tet. Lett. (1998), 39,2319-2320.

Scheme V illustrates a synthetic route for the preparation of compoundsof the present invention where A is carbon, B is nitrogen and X is abond, as well as the introduction of R^(3a) and/or R^(3b).

Intermediate I-5a is prepared by treating the appropriate amine havingthe desired R¹ group with trimethylaluminum under inert atmosphericconditions followed by condensation with the appropriate cyanide havingthe desired R⁰ group. Suitable amines include substituted phenyl amines(e.g., 4-chlorophenyl amine, 4-fluorophenyl amine, 4-bromophenyl amine,4-iodophenyl amine, 4-cyanophenyl amine, and the like) pyridin-2-ylamine, pyridin-3-yl amine, pyridin-4-yl amine, substituted pyridinylamines (e.g., 2-dimethylaminopyridin-5-yl amine, 2-methoxypyridin-5-ylamine, 5-chloropyridin-2-yl amine, 5-methylpyridin-2-yl,5-methoxypyridin-2-yl amine, 3-chloropyridin-4-yl; amine,2-N-morpholinylpyridin-5-yl, and the like), and other commerciallyavailable or easily synthesized substituted or unsubstituted aryl andheteroaryl amines. Suitable cyano compounds include substitutedbenzonitriles (e.g., 2-chlorobenzonitrile, 2-fluorobenzonitrile,2-methoxybenzonitrile, 2-methylbenzonitrile, 2,4-dichlorobenzonitrile,2,4-difluorobenzonitrile, 2-chloro-4-fluorobenzonitrile,2-chloro-4-methylbenzonitrile, 2,4-dimethoxybenzonitrile,2-methyl-4-chlorobenzonitrile, and the like), cyano-substitutedpyridines (e.g., 4-cyano-3-chloropyridine) and other commerciallyavailable or easily synthesized substituted or unsubstituted aryl orheteroaryl nitriles.

Intermediate I-5a may then be condensed with a 3-bromo-2-oxo-propionicacid ester to produce the cyclized 4-hydroxy-4,5-dihydro-1H-imidazoleester I-5b using procedures analogous to those described by Khanna, I.K., et al., in J. Med. Chem., 40, 1634 (1997). For example, the amidineintermediate I-5a is refluxed in a polar solvent (e.g., isopropanol) inthe presence of a mild base (e.g., sodium bicarbonate). Generally, thereaction (i.e., cyclization followed by dehydration) procedes directlyto the desired imidazole ester intermediate I-5c. In some instances, itmay be necessary to dehydrate the initial carbinol condensation productI-5b with an acid catalyst (e.g., toluene sulfonic acid in refluxingtoluene) to provide the desired imidazole ester I-5c.

The imidazole ester I-5c is prepared from the 4-hydroxy-4,5-dihydrointermediate I-5b using standard dehydration procedures well-known tothose skilled in the art. For example, intermediate I-5b may be treatedwith p-toluenesufonic acid monohydrate in refluxing toluene.Alternative, intermediate I-5b may be treated with methanesulfonylchloride in the presence of a base (e.g., triethylamine). The bromogroup may be introduced into intermediate I-5c by treating with brominefollowing a procedure described in J. Het Chem, 34 (3), 765-771 (1997).The bromo group of I-5c may then be converted to a formyl group toproduce intermediate I-5d by first treating intermediate I-5c with astrong base (e.g., n-butyl lithium) followed by treatment with DMF. Theamino functionality may then be introduced using procedures analogous tothose discussed earlier for the pyrazole compounds. For example,intermediate I-5d may be reacted with the desired amine (R⁴—NH₂) in thepresence of NaBH(OAc)₃ to produce intermediate I-5e. The aminointermediate I-5e may then be cyclized to form the lactam by firsthydrolyzing the ester group to its corresponding carboxylic acidfollowed by the formation of the amide linkage using proceduresanalogous to those discussed above for the pyrazole derivatives.Compound I-F may be further modified by attaching pendant R^(3a) and/orR^(3b) groups using procedures analogous to those discussed above. Forexample, treatment of Compound I-F with the desired reagents (R^(2a)—Land/or R^(2a)—L, where L is a leaving group, such a halo group (e.g.,bromo)) in the presence of a base such as KHMDSi.

Scheme VI illustrates the preparation of compounds of the presentinvention where A is carbon, B is nitrogen (imidazole) and X is—C(R^(2a))(R^(2b))—.

The imidazole compound I-H may be prepared using procedures analogous tothose discussed above for the preparation of the pyrazole derivative(I-D). An extra methylene is introduced in the molecule by firstreacting intermediate I-5e with the ylid formed from lithiumhexamethyldisilazide and (methoxymethyl)triphenylphosphonium chloride toproduce the vinyl ether I-6a. The vinyl ether is converted to thecorresponding aldehyde by heating the vinyl ether intermediate in anacidic environment. The amino functionality (R⁴—NH) may then beintroduced and the lactam ring formed using procedures analogous tothose discussed above. As discussed above, the lactam may be formed byfirst hydrolyzing the ester, followed by formation of the amide linkageto produce Compound I-H.

Compounds of Formula I wherein R⁴ is an optionally substitutedpiperidinyl or pyrrolidinyl group can be prepared as shown in SchemeVII.

Removal of the protecting group in Compound I-E can be accomplished bymethods known in the art to give bicyclic amino derivatives such as I-Iwhich can be subsequently reacted with alkyl halides in the presence ofa suitable base such as potassium carbonate in a solvent such as DMF ortreated with acid chlorides or sulfonyl chlorides in the presence of abase such as triethylamine in a non-polar solvent such as CH₂Cl₂ to givecompounds such as I-J. Compound I-E can also be reacted with an aldehydeor ketone derivative in the presence of a reducing agent such asNaBH(OAc)₃ as previously described to produce intermediate I-J.

Compounds of formulae II-A and II-B can be prepared as shown in SchemeVIII.

The pyrazole compound I-E is treated with a suitable reducing agent suchas lithium aluminum hydride or borane (BH₃) in a polar, aprotic solventsuch as THF at temperatures ranging from about 0° C. to about 100° C. togive compounds such as II-A. Compound II-B can be prepared from I-Dusing a similar reduction procedure. The imidazole compounds of formulaII (A is carbon and B is nitrogen) may be prepared using analogousprocedures.

Conventional methods and/or techniques of separation and purificationknown to one of ordinary skill in the art can be used to isolate thecompounds of the present invention, as well as the various intermediatesrelated thereto. Such techniques will be well known to one of ordinaryskill in the art and may include, for example, all types ofchromatography (high pressure liquid chromatography (HPLC), columnchromatography using common adsorbents such as silica gel, andthin-layer chromatography), recrystallization, and differential (i.e.,liquid-liquid) extraction techniques.

The compounds of the present invention may be isolated and used per seor in the form of its pharmaceutically acceptable salt, solvate and/orhydrate. The term “salts” refers to inorganic and organic salts of acompound of the present invention. These salts can be prepared in situduring the final isolation and purification of a compound, or byseparately reacting the compound, or prodrug with a suitable organic orinorganic acid or base and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride,hydroiodide, sulfate, bisufate, nitrate, acetate, trifluoroacetate,oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate,malate, borate, benzoate, lactate, phosphate, hexafluorophosphate,benzene sulfonate, tosylate, formate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. These mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, e.g., Berge, et al., J. Pham. Sci., 66, 1-19 (1977).

The term “prodrug” means a compound that is transformed in vivo to yielda compound of Formula (I) or a pharmaceutically acceptable salt, hydrateor solvate of the compound. The transformation may occur by variousmechanisms, such as through hydrolysis in blood. A discussion of the useof prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound of the present invention contains an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removalof a hydroxyl group of the hemiacetal form of a carbohydrate).

If a compound of the present invention incorporates an amine functionalgroup, a prodrug can be formed by the replacement of a hydrogen atom inthe amine group with a group such as R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY′ wherein Y′ is H,(C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ wherein Y₀ is (C₁-C₄) alkyl and Y₁ is(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃ wherein Y₂ is H or methyl and Y₃is mono-N- or di-N,N-(C₁-C₆) alkylamino, morpholino, piperdin-1-yl orpyrrolidin-1-yl.

The compounds of the present invention may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of the presentinvention as well as mixtures thereof, including racemic mixtures, formpart of the present invention. In addition, the present inventionembraces all geometric and positional isomers. For example, if acompound of the present invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

It is also possible that the intermediates and compounds of the presentinvention may exist in different tautomeric forms, and all such formsare embraced within the scope of the invention. The term “tautomer” or“tautomeric form” refers to structural isomers of different energieswhich are interconvertible via a low energy barrier. For example, protontautomers (also known as prototropic tautomers) include interconversionsvia migration of a proton, such as keto-enol and imine-enamineisomerizations. A specific example of a proton tautomer is the imidazolemoiety where the proton may migrate between the two ring nitrogens.Valence tautomers include interconversions by reorganization of some ofthe bonding electrons.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ¹²³I, ¹²⁵I and ³⁸Cl, respectively.

Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹⁴C) are useful in compound and/or substratetissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent invention can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

Compounds of the present invention are useful for treating diseases,conditions and/or disorders modulated by cannabinoid receptorantagonists; therefore, another embodiment of the present invention is apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention and a pharmaceutically acceptableexcipient, diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexabonagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The compound of the presentinvention is typically formulated into pharmaceutical dosage forms toprovide an easily controllable dosage of the drug and to give thepatient an elegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present invention further provides a method of treating diseases,conditions and/or disorders modulated by cannabinoid receptorantagonists in an animal that includes administering to an animal inneed of such treatment a therapeutically effective amount of a compoundof the present invention or a pharmaceutical composition comprising aneffective amount of a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier. The methodis particularly useful for treating diseases, conditions and/ordisorders modulated by cannabinoid receptor (in particular, CB1receptor) antagonists.

Preliminary investigations have indicated that the following diseases,conditions, and/or disorders are modulated by cannabinoid receptorantagonists: eating disorders (e.g., binge eating disorder, anorexia,and bulimia), weight loss or control (e.g., reduction in calorie or foodintake, and/or appetite suppression), obesity, depression, atypicaldepression, bipolar disorders, psychoses, schizophrenia, behavioraladdictions, suppression of reward-related behaviors (e.g., conditionedplace avoidance, such as suppression of cocaine- and morphine-inducedconditioned place preference), substance abuse, addictive disorders,impulsivity, alcoholism (e.g., alcohol abuse, addiction and/ordependence including treatment for abstinence, craving reduction andrelapse prevention of alcohol intake), tobacco abuse (e.g., smokingaddiction, cessation and/or dependence including treatment for cravingreduction and relapse prevention of tobacco smoking), dementia(including memory loss, Alzheimer's disease, dementia of aging, vasculardementia, mild cognitive impairment, age-related cognitive decline, andmild neurocognitive disorder), sexual dysfunction in males (e.g.,erectile difficulty), seizure disorders, epilepsy, inflammation,gastrointestinal disorders (e.g., dysfunction of gastrointestinalmotility or intestinal propulsion), attention deficit disorder (ADDincluding attention deficit hyperactivity disorder (ADHD)), Parkinson'sdisease, and type II diabetes.

Accordingly, the compounds of the present invention described herein areuseful in treating diseases, conditions, or disorders that are modulatedby cannabinoid receptor antagonists. Consequently, the compounds of thepresent invention (including the compositions and processes usedtherein) may be used in the manufacture of a medicament for thetherapeutic applications described herein.

Other diseases, conditions and/or disorders for which cannabinoidreceptor antagonists may be effective include: premenstrual syndrome orlate luteal phase syndrome, migraines, panic disorder, anxiety,post-traumatic syndrome, social phobia, cognitive impairment innon-demented individuals, non-amnestic mild cognitive impairment, postoperative cognitive decline, disorders associated with impulsivebehaviours (such as, disruptive behaviour disorders (e.g.,anxiety/depression, executive function improvement, tic disorders,conduct disorder and/or oppositional defiant disorder), adultpersonality disorders (e.g., borderline personality disorder andantisocial personality disorder), diseases associated with impulsivebehaviours (e.g., substance abuse, paraphilias and self-mutilation), andimpulse control disorders (e.g., intermittene explosive disorder,kleptomania, pyromania, pathological gambling, and trichotillomania)),obsessive compulsive disorder, chronic fatigue syndrome, sexualdysfunction in males (e.g., premature ejaculation), sexual dysfunctionin females, disorders of sleep (e.g., sleep apnea), autism, mutism,neurodengenerative movement disorders, spinal cord injury, damage of thecentral nervous system (e.g., trauma), stroke, neurodegenerativediseases or toxic or infective CNS diseases (e.g., encephalitis ormeningitis), cardiovascular disorders (e.g., thrombosis), and diabetes.

The compounds of the present invention can be administered to a patientat dosage levels in the range of from about 0.7 mg to about 7,000 mg perday. For a normal adult human having a body weight of about 70 kg, adosage in the range of from about 0.01 mg to about 100 mg per kilogrambody weight is typically sufficient. However, some variability in thegeneral dosage range may be required depending upon the age and weightof the subject being treated, the intended route of administration, theparticular compound being administered and the like. The determinationof dosage ranges and optimal dosages for a particular patient is wellwithin the ability of one of ordinary skill in the art having thebenefit of the instant disclosure. It is also noted that the compoundsof the present invention can be used in sustained release, controlledrelease, and delayed release formulations, which forms are also wellknown to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, 11β-hydroxy steroid dehydrogenase-1 (11β-HSDtype 1) inhibitors, peptide YY₃₋₃₈ or analogs thereof, MCR-4 agonists,cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (suchas sibutramine), sympathomimetic agents, β₃ adrenergic receptoragonists, dopamine agonists (such as bromocriptine),melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melaninconcentrating hormone antagonists, leptin (the OB protein), leptinanalogs, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorecticagents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g.,NPY Y5 receptor antagonists, such as the spiro compounds described inU.S. Pat. Nos. 6,566,367; 6,649,624; 6,638,942; 6,605,720; 6,495,559;6,462,053; 6,388,077; 6,335,345; and 6,326,375; US Publication Nos.2002/0151456 and 2003/036652; and PCT Publication Nos. WO 03/010175. WO03/082190 and WO 02/048152), thyromimetic agents, dehydroepiandrosteroneor an analog thereof, glucocorticoid receptor agonists or antagonists,orexin receptor antagonists, glucagon-like peptide-1 receptor agonists,ciliary neurotrophic factors (such as Axokine™ available from RegeneronPharmaceuticals, Inc., Tarrytown, N.Y. and Procter & Gamble Company,Cincinnati, Ohio.), human agouti-related proteins (AGRP), ghrelinreceptor antagonists, histamine 3 receptor antagonists or inverseagonists, neuromedin U receptor agonists and the like. Otheranti-obesity agents, including the preferred agents set forthhereinbelow, are well known, or will be readily apparent in light of theinstant disclosure, to one of ordinary skill in the art.

Especially preferred are anti-obesity agents selected from the groupconsisting of orlistat, sibutramine, bromocriptine, ephedrine, leptin,pseudoephedrine, PYY₃₋₃₆ or an analog thereof, and2-oxo-N-(5-phenylpyrazinyl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.Preferably, compounds of the present invention and combination therapiesare administered in conjunction with exercise and a sensible diet.

Representative anti-obesity agents for use in the combinations,pharmaceutical compositions, and methods of the invention can beprepared using methods known to one of ordinary skill in the art, forexample, sibutramine can be prepared as described in U.S. Pat. No.4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos.3,752,814 and 3,752,888; orlistat can be prepared as described in U.S.Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; PYY₃₋₃₆(including analogs) can be prepared as described in US Publication No.2002/0141985 and WO 03/027637; and the NPY Y5 receptor antagonist2-oxo-N-(5-phenyl-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamidecan be prepared as described in US Publication No. 2002/0151456. Otheruseful NPY Y5 receptor antagonists include those described in PCTPublication No. 03/082190, such as3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide;3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide;N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),[4′-piperidine]-1′-carboxamide;trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide;trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazoly]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide;trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(1-phenyl4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[1-(2-fluorophenyl-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(I-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]4′-carboxamide;trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide; and pharmaceutically acceptable saltsand esters thereof. All of the above recited U.S. patents andpublications are incorporated herein by reference.

Other suitable pharmaceutical agents that may be administered incombination with the compounds of the present invention include agentsdesigned to treat tobacco abuse (e.g., nicotine receptor partialagonists, bupropion hypochloride (also known under the tradename Zyban™)and nicotine replacement therapies), agents to treat erectiledysfunction (e.g., dopaminergic agents, such as apomorphine), ADD/ADHDagents (e.g., Ritalin™, Strattera™, Concerta™ and Adderall™), and agentsto treat alcoholism, such as opioid antagonists (e.g., naltrexone (alsoknown under the tradename ReVia™) and nalmefene), disulfiram (also knownunder the tradename Antabuse™), and acamprosate (also known under thetradename Campral™)). In addition, agents for reducing alcoholwithdrawal symptoms may also be co-administered, such asbenzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin™). Treatment for alcoholism is preferablyadministered in combination with behavioral therapy including suchcomponents as motivational enhancement therapy, cognitive behavioraltherapy, and referral to self-help groups, including Alcohol Anonymous(AA).

Other pharmaceutical agents that may be useful include antihypertensiveagents; anti-inflammatory agents (e.g., COX-2 inhibitors);antidepressants (e.g., fluoxetine hydrochloride (Prozac™)); cognitiveimprovement agents (e.g., donepezil hydrochloride (Aircept™) and otheracetylcholinesterase inhibitors); neuroprotective agents (e.g.,memantine); antipsychotic medications (e.g., ziprasidone (Geodon™),risperidone (Risperdal™), and olanzapine (Zyprexa™)); insulin andinsulin analogs (e.g., LysPro insulin); GLP-1 (7-37) (insulinotropin)and GLP-1 (7-36)-NH₂; sulfonylureas and analogs thereof: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide®,glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; α2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, A-4166; glitazones: ciglitazone, Actoso®(pioglitazone), englitazone, troglitazone, darglitazone, Avandia®(BRL49653); fatty acid oxidation inhibitors: domoxir, etomoxir;α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose,MDL-25,637, camiglibose, MDL-73,945; β-agonists: BRL 35135, BRL 37344,RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors:L-386,398; lipid-lowering agents: benfluorex: fenfluramine; vanadate andvanadium complexes (e.g., Naglivan®) and peroxovanadium complexes;amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors;somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox,WAG 994, pramlintide (Symlin™), AC 2993, nateglinide, aldose reductaseinhibitors (e.g., zopolrestat), glycogen phosphorylase inhibitors,sorbitol dehydrogenase inhibitors, sodium-hydrogen exchanger type 1(NHE-1) inhibitors and/or cholesterol biosynthesis inhibitors orcholesterol absorption inhibitors, especially a HMG-CoA reductaseinhibitor, or a HMG-CoA synthase inhibitor, or a HMG-CoA reductase orsynthase gene expression inhibitor, a CETP inhibitor, a bile acidsequesterant, a fibrate, an ACAT inhibitor, a squalene synthetaseinhibitor, an anti-oxidant or niacin. The compounds of the presentinvention may also be administered in combination with a naturallyoccurring compound that acts to lower plasma cholesterol levels. Suchnaturally occurring compounds are commonly called nutraceuticals andinclude, for example, garlic extract, Hoodia plant extracts, and niacin.

The dosage of the additional pharmaceutical agent is generally dependentupon a number of factors including the health of the subject beingtreated, the extent of treatment desired, the nature and kind ofconcurrent therapy, if any, and the frequency of treatment and thenature of the effect desired. In general, the dosage range of theadditional pharmaceutical agent is in the range of from about 0.001 mgto about 100 mg per kilogram body weight of the individual per day,preferably from about 0.1 mg to about 10 mg per kilogram body weight ofthe individual per day. However, some variability in the general dosagerange may also be required depending upon the age and weight of thesubject being treated, the intended route of administration, theparticular anti-obesity agent being administered and the like. Thedetermination of dosage ranges and optimal dosages for a particularpatient is also well within the ability of one of ordinary skill in theart having the benefit of the instant disclosure.

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent is administered to a subjectin need of such treatment, preferably in the form of a pharmaceuticalcomposition. In the combination aspect of the invention, the compound ofthe present invention and at least one other pharmaceutical agent (e.g.,anti-obesity agent, nicotine receptor partial agonist, dopaminergicagent, or opioid antagonist) may be administered either separately or inthe pharmaceutical composition comprising both. It is generallypreferred that such administration be oral. However, if the subjectbeing treated is unable to swallow, or oral administration is otherwiseimpaired or undesirable, parenteral or transdermal administration may beappropriate.

According to the methods of the invention, when a combination of acompound of the present invention and at least one other pharmaceuticalagent are administered together, such administration can be sequentialin time or simultaneous with the simultaneous method being generallypreferred. For sequential administration, a compound of the presentinvention and the additional pharmaceutical agent can be administered inany order. It is generally preferred that such administration be oral.It is especially preferred that such administration be oral andsimultaneous. When a compound of the present invention and theadditional pharmaceutical agent are administered sequentially, theadministration of each can be by the same or by different methods.

According to the methods of the invention, a compound of the presentinvention or a combination of a compound of the present invention and atleast one additional pharmaceutical agent (referred to herein as a“combination”) is preferably administered in the form of apharmaceutical composition. Accordingly, a compound of the presentinvention or a combination can be administered to a patient separatelyor together in any conventional oral, rectal, transdermal, parenteral,(for example, intravenous, intramuscular, or subcutaneous)intracistemal, intravaginal, intraperitoneal, intravesical, local (forexample, powder, ointment or drop), or buccal, or nasal, dosage form.

Compositions suitable for parenteral injection generally includepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Suitable aqueous and nonaqueous carriers or diluents (including solventsand vehicles) include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain excipients such as preserving,wetting, emulsifying, and dispersing agents. Prevention of microorganismcontamination of the compositions can be accomplished with variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride, and the like. Prolonged absorption of injectablepharmaceutical compositions can be brought about by the use of agentscapable of delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, a compound of thepresent invention or a combination is admixed with at least one inertexcipient, diluent or carrier. Suitable excipients, diluents or carriersinclude materials such as sodium citrate or dicalcium phosphate or (a)fillers or extenders (e.g., starches, lactose, sucrose, mannitol,silicic acid and the like); (b) binders (e.g., carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like);(c) humectants (e.g., glycerol and the like); (d) disintegrating agents(e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain complex silicates, sodium carbonate and the like); (e)solution retarders (e.g., paraffin and the like); (f) absorptionaccelerators (e.g., quaternary ammonium compounds and the like); (g)wetting agents (e.g., cetyl alcohol, glycerol monostearate and thelike); (h) adsorbents (e.g., kaolin, bentonite and the like); and/or (i)lubricants (e.g., talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate and the like). In the caseof capsules and tablets, the dosage forms may also comprise bufferingagents. Solid compositions of a similar type may also be used as fillersin soft or hard filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene glycols,and the like.

Solid dosage forms such as tablets, dragees, capsules, and granules canbe prepared with coatings and shells, such as enteric coatings andothers well known in the art. They may also contain opacifying agents,and can also be of such composition that they release the compound ofthe present invention and/or the additional pharmaceutical agent in adelayed manner. Examples of embedding compositions that can be used arepolymeric substances and waxes. The drug can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the compound of the present invention or the combination,the liquid dosage form may contain inert diluents commonly used in theart, such as water or other solvents, solubilizing agents andemulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseedoil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seedoil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, or mixtures of thesesubstances, and the like.

Besides such inert diluents, the composition can also includeexcipients, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the compound of the present invention or thecombination, may further comprise carriers such as suspending agents,e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar, and tragacanth, or mixtures of these substances,and the like.

Compositions for rectal or vaginal administration preferably comprisesuppositories, which can be prepared by mixing a compound of the presentinvention or a combination with suitable non-irritabing excipients orcarriers, such as cocoa butter, polyethylene glycol or a suppository waxwhich are solid at ordinary room temperature but liquid at bodytemperature and therefore melt in the rectum or vaginal cavity therebyreleasing the active component(s).

Dosage forms for topical administration of the compounds of the presentinvention and combinations of the compounds of the present inventionwith anti-obesity agents may comprise ointments, powders, sprays andinhalants. The drugs are admixed under sterile condition with apharmaceutically acceptable excipient, diluent or carrier, and anypreservatives, buffers, or propellants that may be required. Ophthalmicformulations, eye ointments, powders, and solutions are also intended tobe induced within the scope of the present invention.

The following paragraphs describe exemplary formulations, dosages, etc.useful for non-human animals. The administration of the compounds of thepresent invention and combinations of the compounds of the presentinvention with anti-obesity agents can be effected orally or non-orally(e.g., by injection).

An amount of a compound of the present invention or combination of acompound of the present invention with an anti-obesity agent isadministered such that an effective dose is received. Generally, a dailydose that is administered orally to an animal is between about 0.01 andabout 1,000 mg/kg of body weight, preferably between about 0.01 andabout 300 mg/kg of body weight.

Conveniently, a compound of the present invention (or combination) canbe carried in the drinking water so that a therapeutic dosage of thecompound is ingested with the daily water supply. The compound can bedirectly metered into drinking water, preferably in the form of aliquid, water-soluble concentrate (such as an aqueous solution of awater-soluble salt).

Conveniently, a compound of the present invention (or combination) canalso be added directly to the feed, as such, or in the form of an animalfeed supplement, also referred to as a premix or concentrate. A premixor concentrate of the compound in an excipient, diluent or carrier ismore commonly employed for the inclusion of the agent in the feed.Suitable carriers are liquid or solid, as desired, such as water,various meals such as alfalfa meal, soybean meal, cottonseed oil meal,linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal,and mineral mixes such as are commonly employed in poultry feeds. Aparticularly effective carrier is the respective animal feed itself;that is, a small portion of such feed. The carrier facilitates uniformdistribution of the compound in the finished feed with which the premixis blended. Preferably, the compound is thoroughly blended into thepremix and, subsequently, the feed. In this respect, the compound may bedispersed or dissolved in a suitable oily vehicle such as soybean oil,corn oil, cottonseed oil, and the like, or in a volatile organic solventand then blended with the carrier. It will be appreciated that theproportions of compound in the concentrate are capable of wide variationsince the amount of the compound in the finished feed may be adjusted byblending the appropriate proportion of premix with the feed to obtain adesired level of compound.

High potency concentrates may be blended by the feed manufacturer withproteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements, which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound of the present invention. The mixtures are thoroughly blendedby standard procedures, such as in a twin shell blender, to ensurehomogeneity.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the compound across thetop of the dressed feed.

Drinking water and feed effective for increasing lean meat depositionand for improving lean meat to fat ratio are generally prepared bymixing a compound of the present invention with a sufficient amount ofanimal feed to provide from about 10⁻³ to about 500 ppm of the compoundin the feed or water.

The preferred medicated swine, cattle, sheep and goat feed generallycontain from about 1 to about 400 grams of a compound of the presentinvention (or combination) per ton of feed, the optimum amount for theseanimals usually being about 50 to about 300 grams per ton of feed. Thepreferred poultry and domestic pet feeds usually contain about 1 toabout 400 grams and preferably about 10 to about 400 grams of a compoundof the present invention (or combination) per ton of feed.

For parenteral administration in animals, the compounds of the presentinvention (or combination) may be prepared in the form of a paste or apellet and administered as an implant, usually under the skin of thehead or ear of the animal in which increase in lean meat deposition andimprovement in lean meat to fat ratio is sought.

In general, parenteral administration involves injection of a sufficientamount of a compound of the present invention (or combination) toprovide the animal with about 0.01 to about 20 mg/kg/day of body weightof the drug. The preferred dosage for poultry, swine, cattle, sheep,goats and domestic pets is in the range of from about 0.05 to about 10mg/kg/day of body weight of drug.

Paste formulations can be prepared by dispersing the drug in apharmaceutically acceptable oil such as peanut oil, sesame oil, corn oilor the like.

Pellets containing an effective amount of a compound of the presentinvention, pharmaceutical composition, or combination can be prepared byadmixing a compound of the present invention or combination with adiluent such as carbowax, carnuba wax, and the like, and a lubricant,such as magnesium or calcium stearate, can be added to improve thepelleting process.

It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, implants may also be madeperiodically during the animal treatment period in order to maintain theproper drug level in the animal's body.

The present invention has several advantageous veterinary features. Forthe pet owner or veterinarian who wishes to increase leanness and/ortrim unwanted fat from pet animals, the instant invention provides themeans by which this may be accomplished. For poultry, beef and swinebreeders, utilization of the method of the present invention yieldsleaner animals that command higher sale prices from the meat industry.

Embodiments of the present invention are illustrated by the followingExamples. It is to be understood, however, that the embodiments of theinvention are not limited to the specific details of these Examples, asother variations thereof will be known, or apparent in light of theinstant disclosure, to one of ordinary skill in the art.

EXAMPLES

Unless specified otherwise, starting materials are generally availablefrom commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wis.),Lancaster Synthesis, Inc. (Windham, N.H.), Acros Organics (Fairlawn,N.J.), Maybridge Chemical Company, Ltd. (Comwall, England), TygerScientific (Princeton, N.J.), and AstraZeneca Pharmaceuticals (London,England).

The acronyms listed below have the following corresponding meanings:

-   -   LiN(TMS)₂—lithium hexamethyldisilazide    -   PS-DIEA—polystyrene-bound diisopropylethylamine    -   AIBN—2,2′-azobisisobutyronitrile    -   HOAt—1-hydroxy-7-azabenzotriazole    -   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

General Experimental Procedures

NMR spectra were recorded on a Varian Unity™ 400 or 500 (available fromVarian Inc., Palo Alto, Calif.) at room temperature at 400 and 500 MHz¹H, respectively. Chemical shifts are expressed in parts per million (δ)relative to residual solvent as an internal reference. The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; br s, broad singlet; v br s, very broad singlet; br m,broad multiplet; 2s, two singlets. In some cases only representative ¹HNMR peaks are given.

Mass spectra were recorded by direct flow analysis using positive andnegative atmospheric pressure chemical ionization (APcI) scan modes. AWaters APcI/MS model ZMD mass spectrometer equipped with Gilson 215liquid handling system was used to carry out the experiments

Mass spectrometry analysis was also obtained by RP-HPLC gradient methodfor chromatographic separation. Molecular weight identification wasrecorded by positive and negative electrospray ionization (ESI) scanmodes. A Waters/Micromass ESI/MS model ZMD or LCZ mass spectrometerequipped with Gilson 215 liquid handling system and HP 1100 DAD was usedto carry out the experiments.

Where the intensity of chlorine or bromine-containing ions aredescribed, the expected intensity ratio was observed (approximately 3:1for ³⁵Cl;/³⁷Cl-containing ions and 1:1 for ⁷⁹Br/⁸¹Br-containing ions)and only the lower mass ion is given. MS peaks are reported for allexamples.

Optical rotations were determined on a PerkinElmer™ 241 polarimeter(available from PerkinElmer Inc., Wellesley, Mass.) using the sodium Dline (λ=589 nm) at the indicated temperature and are reported as follows[α]_(D) ^(temp), concentration (c=g/100 ml), and solvent.

Column chromatography was performed with either Baker™ silica gel (40μm; J. T. Baker, Phillipsburg, N.J.) or Silica Gel 50 (EM Sciences™,Gibbstown, N.J.) in glass columns or in Biotage™ columns (ISC, Inc.,Shelton, Conn.) under low nitrogen pressure. Radial chromatography wasperformed using a Chromatotron™ (Harrison Research).

Preparation of Key Intermediates Preparation of Intermediate1-(2-Chloro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester(I-1a)

To a stirred solution of 2-chlorophenylhydrazine hydrochloride (22.4 g)and potassium carbonate (34.5 g) in ethanol (250 ml) was added diethylacetylenedicarboxylate (20 ml) and the resulting mixture was heated atreflux for 18 hours. The reaction mixture was cooled, 6 N hydrochloricacid (75 ml) and water (500 ml) were added sequentially. The reactionmixture was extracted with ethyl acetate, the organic layer washed withwater, brine, dried (Na₂SO₄) and concentrated in vacuo. The resultinggum was stirred with isopropyl ether (250 ml) to afford the titlecompound (I-1a) as a tan solid, (23 g) after filtering and drying invacuo.

Preparation of Intermediate5Bromo-1-(2-chloro-phenyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethylester (I-1b)

To a stirred solution of1-(2-chloro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl esterI-1a (18.2 g) and phosphorus oxybromide (39 g) in 1,2-dichloroethane(200 ml) was added dimethylformamide (10.5 ml) over a 15-min period. Theresulting mixture was heated at reflux for 3 hours, cooled, then anadditional portion of phosphorus oxybromide (98 g) was added andrefluxing was continued for 20 hours. The black reaction mixture wascooled, poured over ice (150 g) and stirred for 30 minutes. The mixturewas extracted with dichloromethane (2×), the combined organic layersdried over magnesium sulfate and concentrated in vacuo to afford a darkoil. The oil was passed through a 200 g plug of silica gel, eluetingwith 30% hexanes:dichloromethane to afford the title compound I-1b as ayellow solid, 8.3 g.

Preparation of Intermediate5-Bromo-1-(2-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylicacid ethyl ester (I-1c)

To a stirred solution of5-bromo-1-(2-chloro-phenyl)-4-formyl-1H-pyrazole-3-carboxylic acid ethylester (2 g), isopropylamine (0.95 ml) and acetic acid (0.4 ml) in1,2-dichloroethane (16 ml) was added sodium triacetoxyborohydride (1.8g) and the resulting slurry was stirred for 18 hours. The reaction wasdiluted into ethyl acetate, washed with saturated aqueous sodiumbicarbonate, brine, dried (Na₂SO₄) and concentrated in vacuo to affordthe title compound (I-1c) as a golden oil, 2.5 g.

Preparation of Intermediate3-Bromo-2-(2-chloro-phenyl)-5isopropyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one(I-1d)

A solution of5-bromo-1-(2-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3carboxylicacid ethyl ester (2.2 g) and 1 N aqueous sodium hydroxide (33 ml) inethanol (55 ml) was heated at 50° C. for 2 hours. The reaction wascooled, acidified to pH˜2 with concentrated hydrochloric acid andconcentrated to a solid in vacuo. The solids were slurried with ethanol(50 ml), filtered and the filtrate was concentrated in vacuo to afford awhite solid, 2.1 g.

To a stirred solution of the above solid (2.0 g), triethylamine (3 ml)in dichloromethane (22 ml) was added 1-propanephosphoric acid cyclicanhydride (5 ml of 50% solution in ethyl acetate) and the resultingsolution was stirred for 20 hours. The reaction was diluted in ethylacetate, washed with 1 N hydrochloride acid, saturated aqueous sodiumbicarbonate, brine and dried (Na₂SO₄) to afford the title compound(I-1d) as a tan solid, 2.0 g.

Preparation of Intermediate5-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-4-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-1H-pyrazole-3-carboxylicacid ethyl ester (I-3a)

A slurry of sodium hydride (45 mg of 60% in oil) in dimethyl sulfoxide(2 ml) was stirred at 75° C. for 45 minutes, cooled to room temperature,then (2-(trimethylsilyl)-ethoxymethyl)triphenylphosphonium chloride (480mg) was added in one portion to produce a red solution. After 10minutes, a solution of5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-formyl-1H-pyrazole-3-carboxylicacid ethyl ester (218 mg) in dimethylsulfoxide (1 ml) was added dropwiseand the resulting solution was stirred for 1 hour. Saturated aqueousammonium chloride was added and the reaction mixture was partitionedbetween diethyl ether and water. The organic phase was dried (Na₂SO₄)and concentrated in vacuo to afford a purple oil. Silica gelchromatography (30% ethyl acetate/hexanes) afforded the title compound(I-3a) as a golden oil, 210 mg.

Preparation of Intermediate5-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-4-(2-oxo-ethyl)-1H-pyrazole-3-carboxylicacid ethyl ester (I-3b)

A solution of5-(4-chloro-phenyl)-1-(2-chloro-phenyl)-4-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-1H-pyrazole-3-carboxylicacid ethyl ester I-3a (210 mg) in 95:5 acetonitrile:conc. hydrofluoricacid (3 ml) was stirred for 2 hours. The reaction was partitionedbetween saturated aqueous sodium hydrogen carbonate and ethyl acetate.The organic phase was washed with brine, dried (Na₂SO₄) and concentratedin vacuo to afford the title compound (I-3b), which was taken directlyon to the next reaction.

Preparation of Intermediate1-(2-Chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid ethyl ester (I-4a)

A solution of 4-chloropropiophenone (16.9 g, 100 mmol) in diethylether(20 ml) was added to a solution of LiN(TMS)₂ (1 M solution in THF, 100ml, 100 mmol) in diethylether (400 ml) at −78° C. The reaction mixturewas stirred at −78° C. for 0.75 hour, then diethyl oxalate (15 ml, 110mmol) was added dropwise. The reaction mixture was slowly allowed towarm to room temperature and stir for 17 hours. The diethyl ether wasremoved under vacuum and the residue was diluted with diethyl ether. Alight yellow solid precipitated out of solution and was collected byfiltration (9.9 g, 36%). This solid, which was used without furtherpurification, was dissolved in isopropyl alcohol (200 ml), and2-chlorophenylhydrazine (5.9 g, 36.1 mmol) and conc. H₂SO₄ (0.4 ml) wasadded. The reaction mixture was heated under reflux for 17 hours. Aftercooling to room temperature, NaHCO₃ (1 g) was added. The reactionmixture was concentrated under vacuum. The residue was diluted withEtOAc and the organic solution was washed with sat'd aq NaHCO₃ and sat'daq NaCl, dried, filtered, and concentrated in vacuo. The residue wastriturated with cyclohexane to give I-4a as an off-white solid (9.5 g,25%): +APCI MS (M+1) 375.0.

Preparaton of Intermediate4-Bromomethyl-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester (I-4b)

A mixture of1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylicacid ethyl ester I-4a (2.8 g, 7.46 mmol), N-bromosuccinimide (1.6 g,8.95 mmol), AlBN (245 mg, 1.49 mmol) in CCl₄ (60 ml) was heated underreflux for 17 hours. The reaction was cooled to room temperature,filtered to remove any solids, and concentrated under vacuum. The cruderesidue was purified via silica gel chromatorgraphy (Flash 40) using asolvent gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give thedesired product (I-4b) as an amorphous solid (2.2 g, 64%): +APCI MS(M+1) 455.0.

Preparation of Intermediate1-(2-Chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylicacid ethyl ester (I-4c)

A mixture of4-bromomethyl-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-4b (200 mg, 0.44 mmol), isopropyl amine (26 mg, 0.44mmol), K₂CO₃ (182 mg, 1.32 mmol) in CH₃CN (5 ml) was stirred for 17hours at room temperature. The reaction mixture was filtered to removeinsoluble material and concentrated under vacuum. The residue wasdiluted with EtOAc and the organic solution was washed with H₂O andsat'd aq. NaCl, dried, and concentrated in vacua. The crude residue waspurified on SiO₂-gel chromatography using a solvent gradient of 20%EtOAc/hexanes to 75% EtOAc/hexanes to give the product (I-4c) as anamorphous solid (40 mg, 21%): +APCI MS (M+1) 432.2.

Preparation of Intermediate1-(2-Chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylicacid (I-4d)

A solution of1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-4c (32 mg, 0.074 mmol) in a 1:4 solution of 1MKOH/EtOH (10 ml) was stirred at 50° C. for 6 hours and at 37° C. for 72hours. The reaction mixture was treated with conc. HCl until the pH ofthe solution was approximately 1 and then concentrated in vacuo. Theresidue was diluted with EtOH and filtered. The filtrate wasconcentrated under vacuum to give I-4a as a white solid (40 mg, 100%):+APCI MS (M+1) 404.1.

Preparation of Intermediate 2-Chloro-N-(4-chloro-phenyl)-benzamidine(I-5a)

Trimethylaluminum (2M in hexanes, 100 ml, 200 mmol) was added dropwiseto a solution of 4-chloro-phenylamine (18.2 g, 143 mmol) in toluene (550ml) under a N₂ atmosphere at 0° C. The reaction mixture was warmed toroom temperature and stirred for 3.5 hours. A solution of2-chlorobenzonitrile (23.6 g, 171 mmol) in toluene (140 ml) was addedand the reaction mixture was heated at 80° C. for 17 hours, during whichtime it became homogeneous. The reaction mixture was then cooled to roomtemperature and poured over a slurry of silica gel in CHCl₃/methanol(2:1). After filtration, the filter cake was washed with a mixture ofCH₂Cl₂/MeOH (2:1). The combined filtrates were concentrated in vacuo,and the solid yellow residue was triturated with hexanes/ether (2:1).The product I-5a (25.1 g, 66%) was used in the next reaction withoutfurther purification.

Preparation ofIntermediate1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-4-hydroxy-4,5-dihydro-1H-midazole-4-carboxylicacid ethyl ester (I-5b)

A mixture of 2-chloro-N-(4-chloro-phenyl)-benzamidine (I-5a), 25.1 g, 95mmol) and NaHCO₃ (84 g, 189 mmol) in 2-propanol (473 ml) was treatedwith 3-bromo-2-oxo-propionic acid ethyl ester (14.3 ml, 22 g, 113 mmol).The reaction mixture was heated at 80° C. for 17 hours. After cooling toroom temperature, the solvent was removed in vacuo. The residue wasdiluted with CH₂Cl₂ and the organic solution was washed with H₂O, driedover MgSO₄, and concentrated in vacuo to provide the product,1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylicacid ethyl ester I-5b, as a dark red residue (36 g).

Preparation of1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acidethyl ester (I-5c)

The crude1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylicacid ethyl ester (I-5b, 36 g, 94.7 mmol) obtained from the previous stepand p-toluenesulfonic acid monohydrate (4.5 g, 24 mmol) in toluene (630ml) was heated under reflux for 17 hours. The reaction mixture wascooled to room temperature and concentrated in vacuo. The crude residuewas taken up in CH₂Cl₂ and the organic solution was washed with H₂O,sat'd aq. NaHCO₃, and sat'd aq NaCl, dried over MgSO₄ and concentratedin vacuo. The crude residue was purified by plug filtration throughsilica gel using a gradient of 2% EtOAc/CH₂Cl₂ to 10% EtOAc/CH₂Cl₂. Thefractions containing the product were concentrated, and the oily residuewas diluted with 1:3 EtOActhexanes (200 ml). After 1 hour, a solidprecipitated out of solution and was collected by filtration to provide1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acidethyl ester I-5c (18.63 g, 69.7%).

Preparation of5-Bromo-1-(4-chloro-phenyl-2-(2-chloro-phenyl-1H-imidazole-4-carboxylicacid ethyl ester (I-5d)

Bromine (3.6 ml, 0.07 mol) was added to a solution of1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylic acidethyl ester (I-5c, 3.6 g, 0.01 mol) in glacial acetic acid (50 ml) atroom temperature. The reaction mixture was stirred for 17 hours, pouredover ice-water, and treated with 25% aq. NaOH until the orange solutionturned yellow. The aqueous solution was extracted with CH₂Cl₂ (3×) andthe combined extracts were dried and concentrated in vacuo to give thedesired compound I-5d as an oil (4.7 g): +APCI MS (M+1) 441.1; ¹H NMR(CD₃Cl) δ 1.41 (3H, t), 4.43 (2H, q), 7.08-7.12 (2H, m), 7.20-7.40 (7H,m).

Preparation of Intermediate1-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-formyl-1H-imidazole-4-carboxylicacid ethyl ester (I-5e)

To a solution of5-bromo-1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester (I-5d, 4.4 g, 0.01 mmol) in anhydrous THF (100 ml) andunder a N₂ atmosphere at −78° C. was slowly added tert.-butyl lithium(13 ml of 1.7 M solution in pentane, 0.22 mol). After 1 hour at −78° C.,DMF (7.7 ml, 0.1 mmol) was added dropwise. The reaction mixture wasstirred at −78° C. for 2.5 hours, quenched with sat'd aq. NH₄Cl (10 ml),allowed to slowly warm to room temperature, and finally poured intosat'd aq. NaCl. The aqueous solution was extracted with Et₂O (3×) andthe combined organic extracts were dried (Na₂SO₄) and concentrated invacuo. The crude residue was purified via flash chromatography using asolvent gradient of 1:3 EtOAc/hexanes to 1:1 EtOAc/hexanes to give thedesired product I-5e as a pale yellow amorphous glass (2.0 g): +APCI MS(M+1) 389.2; ¹H NMR (CD₂Cl₂) δ 1.41 (3H, t), 4.45 (2H, q), 7.09-7.14(2H, m), 7.24-7.39 (7H, m), 10.50 (1H, s).

The following two intermediates were prepared using procedures analogousto those described above for the synthesis of1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-formyl-1H-imidazole-4-carboxylicacid ethyl ester (I-5e):

2-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-5-formyl-1H-imidazole-4-carboxylicacid ethyl ester (I-5e-2);

2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-formly-1H-imidazole-4-carboxylicacid ethyl ester (I-5e-3).

Preparation of intermediate2-(4-Chloro-phenyl)-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester (I-5f)

A solution of2-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-5-formyl-1H-imidazole-4-carboxylicacid ethyl ester I-5e-2 (1000 mg, 2.68 mmol), cyclopentylamine (251 mg,2.95 mmol), NaBH(OAc)₃ (796 mg, 3.76 mmol) in dichloroethane was stirredfor 17 h at room temperature. The reaction was concentrated in vacuo andthe residue was diluted with CHCl₃. The organic solution was washed withsat'd aq. NaHCO₃ and sat'd aq. NaCl, dried, and concentrated undervacuum. The crude residue was purified on SiO₂-gel (Flash 40s) using asolvent gradient of 30% EtOAc/hexanes to 80% EtOAc/hexanes to give thedesired product (I-5f) as a yellow oil (680 mg, 57%): +APCI MS (M+1)442.2.

Preparation of Intermediate2-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-methoxy-vinyl)-1H-imidazole-4-carboxylicacid ethyl ester (I-5g)

To a solution of (methoxymethyl)triphenylphosphonium chloride (533 mg,1.55 mmol) in THF (10 ml) at 0° C. was added lithiumhexamethyldisilazide (1.55 ml, 1M solution, 1.55 mmol). The reactionmixture was stirred for 0.5 h and cooled to −78° C. A solution of2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-formyl-1H-imidazole-4-carboxylicacid ethyl ester I-5e (408 mg, 1.05 mmol) in THF (5 ml) was slowly addedvia cannula. The reaction mixture was stirred at −78° C. for 5 min, thenwas allowed to warm to room temperature and stir for 3 hours. Thereaction mixture was quenched with H₂O and diluted with EtOAc. Theorganic solution was separated and the aqueous layer was extracted oncewith EtOAc. The combined EtOAc extracts were washed with sat'd aq. NaCl,dried, and concentrated in vacuo. The crude residue was purified on 4 mmchromatotron plates using 1:1 EtOAc/hexanes to give the product (I-5g)as two isomeric compounds (148 mg, 34% and 157 mg, 36%): +APCI MS (M+1)417.2

Preparation of Intermediate2-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-5-(2oxo-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester (I-5h)

A solution of2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-methoxy-vinyl)-1H-imidazole-4-carboxylicacid ethyl ester I-5 g (275 mg, 0.659 mmol) and H₂SO₄ (200 μl) in 5:1THF/H₂O (18 ml) was heated at 70° C. for 3 hours. The reaction mixturewas cooled to room temperature and treated with 1M K₂CO₃ until the pH ofthe reaction mixture was ˜6. The aqueous solution was extracted withCH₂Cl₂ and the combined organic extracts were washed with sat'd aq.NaCl, dried, and concentrated in vacuo to give a mixture of the startingmaterial and product (I-5h): +APCI MS (M+1) 403.3

Preparation of intermediate2-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester (I-5i)

Sodium triacetoxyborohydride (32 mg, 0.152 mmol) was added to a solutionof2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-oxo-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester I-5 h (34 mg, 0.084 mmol), cyclopentylamine (12 μl,0.118 mmol), and acetic acid (5 μl, 0.09 mmol) in 1,2-dichlorethane (2ml) at room temperature. The reaction mixture was quenched with 1N NaOHand extracted with CH₂Cl₂ (3×). The combined CH₂Cl₂ extracts were washedwith sat'd aq NaCl, dried, and concentrated in vacuo. The crude residuewas purified on a 1 mm chromatotron plate using 100% EtOAc to give I-5ias a colorless oil (22 mg): +APCI MS (M+1) 472.2.

Preparation of Intermediate2-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylicacid (I-5i)

To a solution of2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester I-5i (22 mg, 0.46 mmol) in absolute EtOH (2 ml) wasadded 1N KOH (500 μl). The reaction mixture was heated to 85° C. for 4hours and then was concentrated to a quarter fraction of the originalvolume. The pH of the solution was adjusted to approximately 3.5 using10% HCl. The aqueous ethanolic solution was concentrated to dryness togive the I-5i as a solid (20 mg): +APCI MS (M+1) 444.4.

Preparation of Intermediate2-(4-Chloro-phenyl)-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylicacid (I-5k)

A solution of2-(4-chloro-phenyl)-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester I-5f (1.2 g, 2.68 mmol) in 1:2 1M KOH/THF was stirredat 55° C. for 17 hours. The reaction mixture was concentrated undervacuum and acidified to pH˜1 with concentrated hydrochloric acid. Theresidue was slurried in EtOH and filtered to remove KCl. The filtratewas concentrated under vaccum to give I-5 k as an off-white solid (1.26g, 97%): +APCl MS (M+1) 414.0.

Example 1 illustrates the preparation of compounds of the presentinvention where A is nitrogen, B is carbon and X is a bond.

Example 1 Preparation of2-(2-Chloro-phenyl)-5-isopropyl-3-(3,4,5-trifluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one(1A-1)

A nitrogen-purged solution of3-bromo-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-oneI-1d (100 mg), cesium fluoride (85 mg), 3,4,5-trifluorophenylboronicacid (74 mg) and tetrakis(triphenylphosphine)palladium(0) (32 mg) in1,2-dimethoxyethane (1 ml) were stirred in a sealed vial at 80° C. for 6hours. The reaction was cooled and partitioned between ethylacetate/water, the organic phase was dried (Na₂SO₄) and concentrated invacuo to afford an oil. Reverse phase HPLC (gradient of 40% to 100%acetonitrile:0.01% aqueous ammonium hydroxide) afforded the titlecompound (1A-1) as an off-white foam, 19 mg. ¹H NMR in CDCl₃ (ppm): δ7.6-7.4 (m, 4H), 6.78-6.65 (m, 2H), 4.76-4.64 (m, 1H), 4.40 (br s, 2H),1.36 (d, 6H); ms (LCMS) m/z=406.3 (M+1)⁺.

The compounds listed in Table 1 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 1A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates.

TABLE 1

LCMS m/z Ex. No. R⁰ R¹ R⁴ (M + 1)⁺ 1A-2 2-chlorophenyl 2-chlorophenyl—CH(CH₃)₂ 386.3 1A-3 2-chlorophenyl 4-(methoxy-methyl)phenyl —CH(CH₃)₂396.4 1A-4 2-chlorophenyl 2-fluorophenyl —CH(CH₃)₂ 370.3 1A-52-chlorophenyl 2-methoxy-pyridyl-5-yl —CH(CH₃)₂ 383.4 1A-62-chlorophenyl 3-chloro-4-fluorophenyl —CH(CH₃)₂ 404.2 1A-72-chlorophenyl 4-fluoro-3-methylphenyl —CH(CH₃)₂ 384.3 1A-82-chlorophenyl vinyl —CH(CH₃)₂ 302.3 1A-9 2-chlorophenyl4-(trifluoromethyl)-phenyl 2,2,2-trifluoroethyl 460.4 1A-102-chlorophenyl 4-(trifluoromethyl)-phenyl isopropyl 420.4 1A-112-chlorophenyl 4-chlorophenyl ethyl 372.4 1A-12 2-chlorophenyl2-chlorophenyl isopropyl 386.3 1A-13 2-chlorophenyl4-(methoxymethyl)-phenyl isopropyl 396.4 1A-14 2-chlorophenyl2-fluorophenyl isopropyl 370.3 1A-15 2-chlorophenyl 4-chlorophenyl2-fluoroethyl 390.3 1A-16 2-chlorophenyl 4-chlorophenyl2,2-difluoroethyl 408.1 1A-17 2-chlorophenyl 4-chlorophenyl2,2,2-trifluoroethyl 426.3 1A-18 2-chlorophenyl 4-ethoxyphenyl t-butyl410.4 1A-19 2-chlorophenyl 4-ethoxyphenyl i-butyl 410.4 1A-202-chlorophenyl 4-ethoxyphenyl ethyl 382.4 1A-21 2-chlorophenyl4-ethoxyphenyl isopropyl 396.4 1A-22 2-chlorophenyl 4-ethoxyphenyl2,2,2-trifluoroethyl 436.4 1A-23 2-chlorophenyl 4-ethylphenyl t-butyl394.5 1A-24 2-chlorophenyl 4-ethylphenyl i-butyl 394.5 1A-252-chlorophenyl 4-ethylphenyl ethyl 366.4 1A-26 2-chlorophenyl4-ethylphenyl isopropyl 380.4 1A-27 2-chlorophenyl 4-ethylphenyl2,2,2-trifluoroethyl 420.4 1A-28 2-chlorophenyl 4-ethylphenyl2,2-difluoropropyl 416.5 1A-29 2-chlorophenyl 4-isopropoxyphenyl t-butyl424.3 1A-30 2-chlorophenyl 4-isopropoxyphenyl i-butyl 424.3 1A-312-chlorophenyl 4-isopropoxyphenyl ethyl 396.2 1A-32 2-chlorophenyl4-isopropoxyphenyl isopropyl 410.2 1A-33 2-chlorophenyl4-isopropoxyphenyl 2,2,2-trifluoroethyl 450.2 1A-34 2-chlorophenyl4-isopropoxyphenyl 2,2-difluoropropyl 446.3 1A-35 2-chlorophenyl4-t-butylphenyl 2,2,2-trifluoroethyl 448.5 1A-36 2-chlorophenyl4-t-butylphenyl 2,2-difluoropropyl 444.5 1A-37 2-chlorophenyl4-i-propylphenyl 2,2,2-trifluoroethyl 434.5 1A-38 2-chlorophenyl4-i-propylphenyl 2,2-difluoropropyl 430.5

Preparation of2-(2-Chlor-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one(1A-39)

To a stirred solution of2-(2-chloro-phenyl)-5-isopropyl-3-vinyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one1A-8 (42 mg), palladium acetate (3 mg) and 4-chloroiodobenzene (300 mg)were stirred for 18 hours. The reaction was concentrated andchromatographed on silica gel (gradient 30% to 60% ethylacetate/hexanes) to afford the title compound (1A-39), 44 mg. ¹H NMR ind₆-DMSO (ppm): δ 7.78 (d, 1H), 7.63-7.38 (m, 5H), 7.13 (d, 1H), 6.61 (d,1H), 4.62 (s, 2H ), 4.40 (m, 1H), 1.23 (d, 6H); ms (LCMS) m/z=412.3(M+1)⁺.

Example 2 illustrates the preparation of compounds of the presentinvention where A is nitrogen, B is carbon and X is —C(R^(2a))(R^(2b))—.

Example 2 Preparation of3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-6-isopropyl-2,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one(2A-1)

To a stirred solution of I-3b (157 mg), isopropylamine (66 μl), aceticacd (27 μl) in 1,2-dichloroethane (0.5 ml) was added sodiumtriacetoxyborohydride (124 mg). After 1.5 hours, the reaction wasdiluted into ethyl acetate, washed with saturated aqueous sodiumbicarbonate, brine, dried (Na₂SO₄), and concentrated in vacuo to afforda golden foam, which was taken onto the next step without furtherpurification.

The product of the above step and 1 N aqueous sodium hydroxide (2.5 ml)were heated at 50° C. for 2.5 hours. The reaction solution was cooled,acidified to pH˜2 with concentrated hydrochloric add, and concentratedin vacuo. The resulting solid residue was slurried with ethanol (10 ml),filtered, the solids were washed with ethanol, and the combinedfiltrates concentrated in vacuo to afford a white solid, which was takenon to the next step without further puification.

To a stirred solution of the above solid prepared in the above step,triethylamine (0.2 ml) in dichloromethane (3 ml) was added1-propane-phosphoric acid cyclic anhydride (0.34 ml of 50% solution inethyl acetate) and the resulting solution was stirred for 2 hours. Thereaction mixture was diluted with ethyl acetate, washed with 1 Nhydrochloride acid, saturated aqueous sodium bicarbonate, brine, anddried (Na₂SO₄) to afford a golden oil. Silica gel chromatography (60%ethyl acetate/hexanes) afforded the title compound (2A-1) as a whitesolid, 103 mg. ¹H NMR in CDCl₃ (ppm): δ 7.50-7.23 (m, 6H), 7.03 (d, 2H),5.17 (m, 1H), 3.57 (m, 2H), 2.84 (br s, 2H), 1.20 (d, 6H); ms (LCMS)m/z=400.3 (M+1)⁺.

The compounds listed in Table 2 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 2A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates.

TABLE 2

LCMS Ex. m/z No. R⁰ R¹ R⁴ (M + 1)⁺ 2A-2 2-chlorophenyl 4-chlorophenyl2,2,2-trifluoroethyl 440.2 2A-3 2-chlorophenyl 4-chlorophenyl2,2-difluoroethyl 422.3 2A-4 2-chlorophenyl 4-chlorophenyl 2-fluoroethyl404.3 2A-5 2-chlorophenyl 4-(trifluoromethyl)phenyl isopropyl 434.4 2A-62-chlorophenyl 4-chlorophenyl ethyl 386.4 2A-7 2-chlorophenyl4-chlorophenyl

426.4 2A-8 2-chlorophenyl 4-chlorophenyl

412.4 2A-9 2-chlorophenyl 4-chlorophenyl t-butyl 414.4 2A-102-chlorophenyl 4-chlorophenyl i-butyl 414.4 2A-11 2-chlorophenyl4-chlorophenyl 2,2-difluoropropyl 436.3 2A-12 2-chlorophenyl4-chlorophenyl

454.5 2A-13 2-chlorophenyl 4-chlorophenyl 2-methoxy-2-methylpropyl 444.42A-14 2-chlorophenyl 4-ethylphenyl 2,2-difluoropropyl 430.5 2A-152-chlorophenyl 4-ethylphenyl isopropyl 394.5 2A-16 2-chlorophenyl4-ethylphenyl t-butyl 408.5 2A-17 2-chlorophenyl 4-ethylphenyl i-butyl408.4 2A-18 2-chlorophenyl 4-ethylphenyl 2,2,2-trifluoroethyl 434.42A-19 2-chlorophenyl 4-ethylphenyl ethyl 380.4 2A-20 2-chlorophenyl4-isopropylphenyl 2,2-difluoropropyl 2A-21 2-chlorophenyl4-isopropylphenyl 2,2,2-trifluoroethyl 448.5 2A-22 2-methylphenyl4-chlorophenyl 2,2,2-trifluoroethyl 420.4 2A-23 2-methylphenyl4-chlorophenyl 2,2-difluoropropyl 416.4

Example 3 Preparation of3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one(3A-1)

A mixture of1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-(isopropylamino-methyl)-1H-pyrazole-3-carboxylicacid I-4d (40 mg, 0.074 mmol), EDC (28 mg, 0.148 mmol), HOAt (20 mg,0.148 mmol), and triethylamine (0.02 ml, 0.148 mmol) in CH₂Cl₂ (10 ml)was stirred at room temperature for 17 hours. The reaction mixture waswashed with sat'd aq NaHCO₃, sat'd aq NaCl, dried and concentrated invacuo. The crude residue was diluted with cyclohexane and stirred for 17hours. A solid precipitated out of solution and was collected byfiltration to give 3A-1 (11 mg, 38%): +APCl MS (M+1) 386.1; ¹H NMR(CDCl₃) δ 7.50-7.38 (m, 4H), 7.26 (d, 2H, J=9.6 Hz), 7.06 (d, 2H), 4.69(m, 1H), 1.3 (d, 6H, J=6.65 Hz).

The compounds listed in Table 3 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 3A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates.

TABLE 3

Ex. +APCI MS No. R⁰ R¹ R^(3a) R^(3b) R⁴ (M + 1) 3A-2 2-chlorophenyl4-methoxyphenyl H H

408.2 3A-3 2-chlorophenyl 4-methoxyphenyl H H

422.4 3A-4 2-chlorophenyl 4-chlorophenyl H H

400.0 3A-5 2-chlorophenyl 4-chlorophenyl H H

398.2 3A-6 2-chlorophenyl 4-chlorophenyl H H

412.3 3A-7 2,4-dichlorophenyl 4-chlorophenyl H H

420.0 3A-8 2,4-dichlorophenyl 4-chlorophenyl H H

434.1 3A-9 4-chlorophenyl 2-chlorophenyl H H

386.1 3A-10 4-chlorophenyl 2-chlorophenyl H H

412.4 3A-11 4-chlorophenyl 2-chloro-phenyl H H

426.4 3A-12 4-chlorophenyl 2-chlorophenyl H H

438.1 3A-13 4-chlorophenyl 2-fluorophenyl H H

396.4 3A-14 4-chlorophenyl 2-fluorophenyl H H

410.5 3A-15 4-chlorophenyl 2-chlorophenyl H H

427.3 3A-16 2-chlorophenyl 4-chlorophenyl H H

427.3(M + 1 -Boc) 3A-17 4-chlorophenyl 2-chlorophenyl H H

527.1 3A-18 4-chlorophenyl 2-chlorophenyl H H

513.1

Example 4 illustrates the preparation of compounds of the presentinvention where A is carbon, B is nitrogen (imidazole derivatives), andX is a bond.

Example 4 Preparation of2-(4-Chloro-phenyl)-5-cyclopentyl-1-(2-fluoro-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one(4A-1)

A mixture of2-(4-chloro-phenyl-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylicacid I-5 k (1.2 g, 2.59 mmol), EDC (994 mg, 5.18 mmol), HOAt (704 mg,5.18 mmol), and triethylamine (1.1 ml, 7.76 mmol) in CH₂Cl₂ (200 ml) wasstirred for 17 hours at room temperature. The reaction mixture waswashed with sat'd aq NaHCO₃ and sat'd aq. NaCl, dried and concentratedin vacuo. The crude residue was purified on SiO₂-gel using a solventgradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give 4A-1 as awhite solid (752 mg, 73%): +APCI MS (M+1) 396.2; ¹H NMR (CDCl₃): δ7.61-7.59 (m, 2H), 7.42-7.37 (m, 6H), 4.60 (m, 1H), 4.50 (s, 2H), 2.0(m, 2H), 1.8-1.65 (m, 6H).

The compounds listed in Table 4 below were prepared using proceduresanalogous to those described above for the synthesis of Compound 4A-1using the appropriate starting materials which are availablecommercially, prepared using preparations well-known to those skilled inthe art, or prepared in a manner analogous to routes described above forother intermediates. The compounds listed below were isolated initiallyas their free base and then converted to its corresponding hydrochloridesalt prior to in vivo testing (if tested in vivo).

TABLE 4

+ES MS Ex. No. R⁰ R¹ R (M + 1) 4A-2 4-chlorophenyl 2,4-dichlorophenyl

446.0 4A-3 4-chlorophenyl 2,4-dichlorophenyl

460.0 4A-4 4-chlorophenyl 2,4-dichlorophenyl —CH₂CF₃ 460.0 4A-54-chlorophenyl 2-chlorophenyl

386.3 4A-6 4-chlorophenyl 2-chlorophenyl

412.2 4A-7 4-chlorophenyl 2-chlorophenyl

426.0 4A-8 4-chlorophenyl 2-fluorophenyl

410.2 4A-9 4-chlorophenyl 2-fluorophenyl

424.3 4A-10 4-fluorophenyl 2-fluorophenyl

380.2 4A-11 4-fluorophenyl 2-chlorophenyl

396.2 4A-12 2-chlorophenyl 4-chlorophenyl

412.2 4A-13 2-chlorophenyl 4-chlorophenyl

426.2 4A-14 2,4-dichlorophenyl 4-chlorophenyl

460.2

Example 5 illustrates the preparation of compounds of the presentinvention where A is carbon, B is nitrogen, and X is—C(R^(2a))(R^(2b))—.

Example 5 Preparation of2-(4-Chloro-phenyl)-1-(2-chloro-phenyl)-5-cyclopentyl-1,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-4-one(5A-1)

A mixture of2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylicacid I-5j (20 mg, 0.046 mmol), EDC (19 mg, 0.1 mmol), HOAt (13 mg, 0.1mmol), and triethylamine (14 μl, 0.1 mmol) in 1,2-dichloroethane (20 ml)was stirred for 17 hours at room temperature. The reaction mixture waswashed with sat'd aq NaHCO₃ and the aqueous bicarbonate solution wasback extracted once with CH₂Cl₂. The combined CH₂Cl₂ extracts were driedand concentrated in vacuo. The residue was dissolved in diethyl ether (1ml) and several drops of 4M HCl in dioxane were added. The organicsolution was decanted and additional ether was added. The mixture wasstirred for several minutes and the solvent decanted again. The residuewas dried under vacuum to give the desired produce 5A-1 as a colorlesssolid: +APCl MS (M+1) 426.3; ¹H NMR (CDCl₃): δ 7.62-7.57 (m, 1H),7.53-7.47 (m, 1H), 7.44-7.39 (m, 1H), 7.37-7.33 (m, 2H), 7.32-7.28 (m,1H), 7.24-7.19 (m, 2H), 5.16-5.06 (m, 1H), 3.56-3.50 (m, 2H) 3.2-3.17(m, 2H), 2.71-2.56 (m, 2H), 1.92-1.83 (m, 2H), 1.76-1.46 (m, 4H).

Example 6 illustrates the preparation of compounds of the presentinvention where A is nitrogen, B is carbon, X is a bond, and R^(3a),R^(3b) are hydrogen, alkyl, and arylalkyl.

Example 6 Preparation of3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4-methyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one(6A-1)

To a solution of3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one3A-1 (19 mg, 0.05 mmol) in THF (0.5 ml) at −78° C. was added LiHMDSi (55μl, 0.055 mmol). A deep blue-black solution was formed. The reactionmixture was stirred for 0.17 hour and then iodomethane (4.4 μl, 0.07mmol) was added dropwise. The reaction mixture was stirred at −78° C.for 0.25 h (until a yellow color formed) and at room temperature for 2hours, quenched with sat'd aq NH₄Cl, and extracted with EtOAc. Theorganic solution was washed with sat'd aq NaCl, dried, and concentratedin vacuo. The residue was purified on 1 mm chromatotron plates using a1:1 EtOAc/hexane solution to give 6A-1 as a white solid (3.2 mg, 14%);+ES MS (M+1) 400.3; ¹H NMR (CDCl₃): δ 7.4-7.3 (m, 4H), 7.28-7.24 (m,2H), 7.1-7.06 (m, 2H), 4.84-4.77 (m, 1H), 4.37-4.27 (m, 1H), 1.48-1.4(m, 9H).

The compounds in Table 6 below were prepared using procedures analogousto those described above for the synthesis of Compound 6A-1 using theappropriate starting materials which are available commercially,prepared using preparations well-known to those skilled in the art, orprepared in a manner analogous to routes described above for otherintermediates.

TABLE 6

Ex. +ES MS No. R⁰ R¹ R^(3a) R^(3b) R⁴ (M + H) 6A-2 2-chlorophenyl4-chlorophenyl

H

476.3 6A-3 2-chlorophenyl 4-chlorophenyl

566.4

Example 7 illustrates the preparation of compounds of the presentinvention where A is nitrogen, B is carbon, X is a bond, and R⁴ ispyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl.

Example 7 Preparation of3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-(1-isopropyl-pipendin-4-yl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one(7A-1)

A solution of4-[3-(4chloro-phenyl)-2-(2-chloro-phenyl)-6-oxo-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester 3A-17 (80 mg, 0.152 mmol) in 1:5 conc HCl/EtOH (6ml) was stirred at room temperature for 2 hours. The reaction mixturewas concentrated in vacuo to give a white solid.

A mixture of the product obtained from the preceding step (30 mg, 0.065mmol), 2-bromopropane (24 mg, 0.194 mmol), K₂CO₃ (45 mg, 0.323 mmol) inDMF (2 ml) was stirred at room temperature for 17 hours. The reactionmixture was diluted with EtOAc and washed with H₂O and sat'd aq NaCl,dried, and concentrated in vacuo. The crude residue was azeotroped oncewith heptane to remove any DMF and purified via SiO₂-gel chromatographyusing 5% Et₂NH/EtOAc to give an oil. ¹H NMR (CDCl₃): δ 7.62-7.45 (m,4H), 7.39-7.32 (d, 2H), 7.23-7.2 (d, 2H), 4.60 (s, 2H), 4.18 (m, 1H),3.10-3.03 (m, 1H), 1.96-1.90 (m, 4H), 1.30-1.25 (m, 4H), 1.09-1.07 (d,6H).

The product from the above reaction was stirred in 4M HCl/dioxane (1 mL)for 0.25 hour and concentrated under vacuum to give 7A-1 as an amorphoussolid (2 mg, 6%).

The compounds in Table 7 below were prepared using procedures analogousto those described above for the synthesis of Compound 7A-1 using theappropriate starting materials which are available commercially,prepared using preparations well-known to those skilled in the art, orprepared in a manner analogous to routes described above for otherintermediates. The compounds listed below were generally isolated as thefree base and then converted to their corresponding hydrochloride saltsprior to in vivo testing (if tested in vivo).

TABLE 7

Ex. +ES MS No. R⁰ R¹ R^(3a) R^(3b) R⁴ (M + H) 7A-2 4-chlorophenyl2-chlorophenyl H H

469.2 7A-3 4-chlorophenyl 2-chlorophenyl H H

455.2 7A-4 4-chlorophenyl 2-chlorophenyl H H

469.1 7A-5 4-chlorophenyl 2-chlorophenyl H H

455.1 7A-6 4-chlorophenyl 2-chlorophenyl H H

455.3

Example 8 illustrates the preparation of compounds of the presentinvention having Formula (II) or (IV).

Example 8 Preparation of3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole(8A-1)

A solution of3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one3A-1 (7 mg, 0.018 mmol) and BH₃THF (166 ml, 166 mmol) was stirred atroom temperature for 1 hour and at 50° C. for 17 hours. After thereaction mixture was cooled to room temperature, MeOH (5 ml) was added.The reaction mixture was heated under reflux for 2 h, cooled to roomtemperature, and concentrated in vacuo. The residue was diluted with 4 MHCl/dioxanes (1 ml) and concentrated under vacuum. The residue wasdissolved in CH₂Cl₂ and hexanes were added to precipitate 8A-1 as acolorless solid (2 mg, 27%): +APCl MS (M+H) 372.5; ¹H NMR (CD₃OD): δ7.59-7.43 (m, 4H), 7.38 (d, 2H), 7.20 (d, 2H), 4.80-4.65 (m, 2H),3.91-3.82 (m, 1H), 3.68-3.55 (m, 2H), 1.52 (d, 6H).

The compounds in Table 8 below were prepared using procedures analogousto those described above for the synthesis of Compound 8A-1 using theappropriate starting materials which are available commercially,prepared using preparations well-known to those skilled in the art, orprepared in a manner analogous to routes described above for otherintermediates. The compounds listed below were generally isolated as thefree base and then converted to their corresponding hydrochloride saltsprior to in vivo testing (if tested in vivo).

TABLE 8

Ex. MS No. R⁰ R¹ R⁴ (MH)⁺ 8A-2 4-chlorophenyl 2-fluorophenyl

396.5 8A-3 2,4-dichlorophenyl 4-chlorophenyl

434.4

Pharmacological Testing

The utility of the compounds of the present invention in the practice ofthe instant invention can be evidenced by activity in at least one ofthe protocols described hereinbelow. The following acronyms are used inthe protocols described below.

BSA—bovine serum albumin

DMSO—dimethylsulfoxide

EDTA—ethylenediamine tetracetic acid

PBS—phosphate-buffered saline

EGTA—ethylene glycol-bis(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid

GDP—guanosine diphosphate

sc—subcutaneous

po—orally

ip—intraperitoneal

icv—intra cerebro ventricular

iv—intravenous

[³H]SR141716A-radiolabeledN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride available from Amersham Biosciences, Piscataway, N.J.

[³H]CP-55940-radiolabled5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)-cyclohexyl]-phenolavailable from NEN Life Science Products, Boston, Mass.

AM251-N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4iodophenyl)-4-methyl-1H-pyrazole-3-carboxamideavailable from Tocris™, Ellisville, Mo.

All of the compounds listed in the Example section above were tested inthe CB-1 receptor binding assay below. The compounds provided a range ofbinding activities from 0.6 nM-2500 nM.

Those compounds having an activity <20 nM were then tested in the CB-1GTPγ [³⁵S] Binding Assay and the CB-2 binding assay described below inthe Biological Binding Assays section. Selected compounds were thentested in vivo using one or more of the functional assays described inthe Biological Functional Assays section below.

In Vitro Biological Assays

Bioassay systems for determining the CB-1 and CB-2 binding propertiesand pharmacological activity of cannabinoid receptor ligands aredescribed by Roger G. Pertwee in “Pharmacology of Cannabinoid ReceptorLigands” Current Medicinal Chemistry, 6, 635-664 (1999) and in WO92/02640 (U.S. application Ser. No. 07/564,075 filed Aug. 8, 1990,incorporated herein by reference).

The following assays were designed to detect compounds that inhibit thebinding of [³H] SR141716A (selective radiolabeled CB-1 ligand) and [³H]5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropy)-cyclohexyl]-phenol;radiolabeled CB-1/CB-2 ligand) to their respective receptors.

Rat CB-1 Receptor Binding Protocol

PelFreeze brains (available from Pel Freeze Biologicals, Rogers, Ark.)were cut up and placed in tissue preparation buffer (5 mM Tris HCl,pH=7.4 and 2 mM EDTA), polytroned at high speed and kept on ice for 15minutes. The homogenate was then spun at 1,000×g for 5 minutes at 4° C.The supematant was recovered and centrifuged at 100,000×G for 1 hour at4° C. The pellet was then re-suspended in 25 ml of TME (25 nM Tris,pH=7.4, 5 mM MgCl₂, and 1 mM EDTA) per brain used. A protein assay wasperformed and 200 μl of tissue totaling 20 μg was added to the assay.

The test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO andTME) and then 25 μl were added to a deep well polypropylene plate. [³H]SR141716A was diluted in a ligand buffer (0.5% BSA plus TME) and 25 μlwere added to the plate. A BCA protein assay was used to determine theappropriate tissue concentration and then 200 μl of rat brain tissue atthe appropriate concentration was added to the plate. The plates werecovered and placed in an incubator at 20° C. for 60 minutes. At the endof the incubation period 250 μl of stop buffer (5% BSA plus TME) wasadded to the reaction plate. The plates were then harvested by Skatrononto GF/B filtenmats presoaked in BSA (5 mg/ml) plus TME. Each filterwas washed twice. The filters were dried overnight. In the morning thefilters were counted on a Wallac Betaplate™ counter (available fromPerkinElmer Life Sciences™, Boston, Mass.).

Human CB-1 Receptor Binding Protocol

Human embryonic kidney 293 (HEK 293) cells transfected with the CB-1receptor cDNA (obtained from Dr. Debra Kendall, University ofConnecticut) were harvested in homogenization buffer (10 mM EDTA, 10 mMEGTA, 10 mM Na Bicarbonate, protease inhibitors; pH=7.4), andhomogenized with a Dounce Homogenizer. The homogenate was then spun at1,000×g for 5 minutes at 4° C. The supernatant was recovered andcentrifuged at 25,000×G for 20 minutes at 4° C. The pellet was thenre-suspended in 10 ml of homogenization buffer and re-spun at 25,000×Gfor 20 minutes at 4° C. The final pellet was re-suspended in 1 ml of TME(25 mM Tris buffer (pH=7.4) containing 5 mM MgCl₂ and 1 mM EDTA). Aprotein assay was performed and 200 μl of tissue totaling 20 μg wasadded to the assay.

The test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO andTME) and then 25 μl were added to a deep well polypropylene plate. [³H]SR141716A was diluted in a ligand buffer (0.5% BSA plus TME) and 25 μlwere added to the plate. The plates were covered and placed in anincubator at 30° C. for 60 minutes. At the end of the incubation period250 μl of stop buffer (5% BSA plus TME) was added to the reaction plate.The plates were then harvested by Skatron onto GF/B filtermats presoakedin BSA (5 mg/ml) plus TME. Each filter was washed twice. The filterswere dried overnight. In the morning the filters were counted on aWallac Betaplate™ counter (available from PerkinElmer Life Sciences™,Boston, Mass.).

CB-2 Receptor Binding Protocol

Chinese hamster ovary-K1 (CHO-K1) cells transfected with CB-2 cDNA(obtained from Dr. Debra Kendall, University of Connecticut) wereharvested in tissue preparation buffer (5 mM Tris-HCl buffer (pH=7.4)containing 2 mM EDTA), polytroned at high speed and kept on ice for 15minutes. The homogenate was then spun at 1,000×g for 5 minutes at 4° C.The supematant was recovered and centrifuged at 100,000×G for 1 hour at4° C. The pellet was then re-suspended in 25 ml of TME (25 mM Trisbuffer (pH=7.4) containing 5 mM MgCl₂ and 1 mM EDTA) per brain used. Aprotein assay was performed and 200 μl of tissue totaling 10 μg wasadded to the assay.

The test compounds were diluted in drug buffer (0.5% BSA, 10% DMSO, and80.5% TME) and then 25 μl were added to the deep well polypropyleneplate. [³H]5-(1,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenolwas diluted a ligand buffer (0.5% BSA and 99.5% TME) and then 25 μl wereadded to each well at a concentration of 1 nM. A BCA protein assay wasused to determine the appropriate tissue concentration and 200 μl of thetissue at the appropriate concentration was added to the plate. Theplates were covered and placed in an incubator at 30° C. for 60 minutes.At the end of the incubation period 250 μl of stop buffer (5% BSA plusTME) was added to the reaction plate. The plates were then harvested bySkatron format onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME.Each filter was washed twice. The filters were dried overnight. Thefilters were then counted on the Wallac Betaplate™ counter.

CB-1 GTPγ [³⁵S] Binding Assay

Membranes were prepared from CHO-K1 cells stably transfected with thehuman CB-1 receptor cDNA. Membranes were prepared from cells asdescribed by Bass et al, in “Identification and characterization ofnovel somatostatin antagonists,” Molecular Pharmacology, 50, 709-715(1996). GTPγ [³⁵S] binding assays were performed in a 96 wellFlashPlate™ format in duplicate using 100 pM GTPγ[³⁵S] and 10 μgmembrane per well in assay buffer composed of 50 mM Tris HCl, pH 7.4, 3mM MgCl₂, pH 7.4, 10 mM MgCl₂, 20 mM EGTA, 100 mM NaCl, 30 μM GDP, 0.1%bovine serum albumin and the following protease inhibitors: 100 μg/mlbacitracin, 100 μg/ml benzamidine, 5 μg/ml aprotinin, 5 μg/ml leupeptin.The assay mix was then incubated with increasing concentrations ofantagonist (10⁻¹⁰ M to 10⁻⁵ M) for 10 minutes and challenged with thecannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(10 μM). Assays were performed at 30° C. for one hour. The FlashPlates™were then centrifuged at 2000×g for 10 minutes. Stimulation of GTPγ[³⁵S]binding was then quantified using a Wallac Microbeta.EC₅₀ calculationsdone using Prism™ by Graphpad.

Inverse agonism was measured in the absense of agonist.

CB-1 FLIPR-based Functional Assay Protocol

CHO-K1 cells co-transfected with the human CB-1 receptor cDNA (obtainedfrom Dr. Debra Kendall, University of Connecticut) and the promiscuousG-protein G16 were used for this assay. Cells were plated 48 hours inadvance at 12500 cells per well on collagen coated 384 well black clearassay plates. Cells were incubated for one hour with 4 μM Fluo-4 AM(Molecular Probes) in DMEM (Gibco) containing 2.5 mM probenicid andpluronic acid (0.04%). The plates were then washed 3 times withHEPES-buffered saline (containing probenicid; 2.5 mM) to remove excessdye. After 20 min the plates were added to the FLIPR individually andfluorescence levels was continuously monitored over an 80 s period.Compound additions were made simultaneously to all 384 wells after 20 sof baseline. Assays were performed in triplicate and 6 pointconcentration-response curves generated. Antagonist compounds weresubsequently challenged with 3 μM WIN 55,212-2 (agonist). Data wereanalyzed using Graph Pad Prism.

Detection of Inverse Agonists

The following cyclic-AMP assay protocol using intact cells was used todetermine inverse agonist activity.

Cells were plated into a 96-well plate at a plating density of10,000-14,000 cells per well at a concentration of 100 μl per well. Theplates were incubated for 24 hours in a 37° C. incubator. The media wasremoved and media lacking serum (100 μl) was added. The plates were thenincubated for 18 hours at 37° C.

Serum free medium containing 1 mM IBMX was added to each well followedby 10 μl of test compound (1:10 stock solution (25 mM compound in DMSO)into 50% DMSO/PBS) diluted 10× in PBS with 0.1% BSA. After incubatingfor 20 minutes at 37° C., 2 μM of Forskolin was added and then incubatedfor an additional 20 minutes at 37° C. The media was removed, 100 μl of0.01N HCl was added and then incubated for 20 minutes at roomtemperature. Cell lysate (75 μl) along with 25 μl of assay buffer(supplied in FlashPlate™ CAMP assay kit available from NEN Life ScienceProducts Boston, Mass.) into a Flashplate. cAMP standards and cAMPtracer were added following the kit's protocol. The flashplate was thenincubated for 18 hours at 4° C. The content of the wells were aspiratedand counted in a Scintillation counter.

In Vivo Biological Assays

Cannabinoid agoinists such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenolhave been shown to affect four characteristic behaviors in mice,collectively known as the Tetrad. For a description of these behaviorssee: Smith, P. B., et al. in “The pharmacological activity ofanandamide, a putative endogenous cannabinoid, in mice.” J. Pharmacol.Exp. Ther., 270 (1), 219-227 (1994) and Wiley, J., et al. in“Discriminative stimulus effects of anandamide in rats,” Eur. J.Pharmacol., 276 (1-2), 49-54 (1995). Reversal of these activities in theLocomotor Activity, Catalepsy, Hypothermia, and Hot Plate assaysdescribed below provides a screen for in vivo activity of CB-1antagonists.

All data is presented as % reversal from agonist alone using thefollowing formula: (5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol/agonist−vehicle/agonist)/(vehicle/vehicle−vehicle/agonist).Negative numbers indicate a potentiation of the agonist activity ornon-antagonist activity. Positive numbers indicate a reversal ofactivity for that particular test.

Locomotor Activity

Male ICR mice (n=6) (17-19 g, Charles River Laboratories, Inc.,Wilmington, Mass.) were pre-treated with test compound (sc, po, ip, oricv). Fifteen minutes later, the mice were challenged with5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Twenty-five minutes after the agonist injection, the mice wereplaced in clear acrylic cages (431.8 cm×20.9 cm×20.3 cm) containingclean wood shavings. The subjects were allowed to explore surroundingsfor a total of about 5 minutes and the activity was recorded by infraredmotion detectors (available from Coulbourn Instruments™, Allentown, Pa.)that were placed on top of the cages. The data was computer collectedand expressed as “movement units.”

Catalepsy

Male ICR mice (n=6)(17-19 g upon arrival) were pre-treated with testcompound (sc, po, ip or icv). Fifteen minutes later, the mice werechallenged with5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Ninety minutes post injection, the mice were placed on a 6.5 cmsteel ring attached to a ring stand at a height of about 12 inches. Thering was mounted in a horizontal orientation and the mouse was suspendedin the gap of the ring with fore- and hind-paws gripping the perimeter.The duration that the mouse remained completely motionless (except forrespiratory movements) was recorded over a 3-minute period.

The data were presented as a percent immobility rating. The rating wascalculated by dividing the number of seconds the mouse remainsmotionless by the total time of the observation period and multiplyingthe result by 100. A percent reversal from the agonist was thencalculated.

Hypothermia

Male ICR mice (n=5) (17-19 g upon arrival) were pretreated with testcompounds (sc, po, ip or icv). Fifteen minutes later, mice werechallenged with the cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Sixty-five minutes post agonist injection, rectal bodytemperatures were taken. This was done by inserting a small thermostatprobe approximately 2-2.5 cm into the rectum. Temperatures were recordedto the nearest tenth of a degree

Hot Plate

Male ICR mice (n=7) (17-19 g upon arrival) are pre-treated with testcompounds (sc, po, ip or iv). Fifteen minutes later, mice werechallenged with a cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Forty-five minutes later, each mouse was tested for reversal ofanalgesia using a standard hot plate meter (Columbus Instruments). Thehot plate was 10″×10″×0.75″ with a surrounding clear acrylic wall.Latency to kick, lick or flick hindpaw or jump from the platform wasrecorded to the nearest tenth of a second. The timer was experimenteractivated and each test had a 40 second cut off. Data were presented asa percent reversal of the agonist induced analgesia.

Food Intake

The following screen was used to evaluate the efficacy of test compoundsfor inhibiting food intake in Sprague-Dawley rats after an overnightfast.

Male Sprague-Dawley rats were obtained from Charles River Laboratories,Inc. (Wilmington, Mass.). The rats were individually housed and fedpowdered chow. They were maintained on a 12 hour light/dark cycle andreceived food and water ad libitum. The animals were acclimated to thevivarium for a period of one week before testing was conducted. Testingwas completed during the light portion of the cycle.

To conduct the food intake efficacy screen, rats were transferred toindividual test cages without food the afternoon prior to testing, andthe rats were fasted overnight. After the overnight fast, rats weredosed the following morning with vehicle or test compounds. A knownantagonist was dosed (3 mg/kg) as a positive control, and a controlgroup received vehicle alone (no compound). The test compounds weredosed at ranges between 0.1 and 100 mg/kg depending upon the compound.The standard vehicle was 0.5% (w/v) methylcellulose in water and thestandard route of administration was oral. However, different vehiclesand routes of administration were used to accommodate various compoundswhen required. Food was provided to the rats 30 minutes after dosing andthe Oxymax automated food intake system (Columbus Instruments, Columbus,Ohio.) was started. Individual rat food intake was recorded continuouslyat 10-minute intervals for a period of two hours. When required, foodintake was recorded manually using an electronic scale; food was weighedevery 30 minutes after food was provided up to four hours after food wasprovided. Compound efficacy was determined by comparing the food intakepattern of compound-treated rats to vehicle and the standard positivecontrol.

Alcohol Intake

The following protocol evaluates the effects of alcohol intake inalcohol preferring (P) female rats (bred at Indiana University) with anextensive drinking history. The following references provide detaileddescriptions of P rats: Li ,T.-K., et al., “Indiana selection studies onalcohol related behaviors” in Development of Animal Models asPharmacogenetic Tools (eds McClearn C. E., Deitrich R. A. and Erwin V.G.), Research Monograph 6, 171-192 (1981) NIAAA, ADAMHA, Rockville, Md.;Lumeng, L, et al., “New strains of rats with alcohol preference andnonpreference” Alcohol And Aldehyde Metabolizing Systems, 3, AcademicPress, New York, 537-544 (1977); and Lumeng, L, et al., “Differentsensitivities to ethanol in alcohol-preferring and -nonpreferring rats,”Pharmacol. Biochem Behav., 16, 125-130 (1982).

Female rats were given 2 hours of access to alcohol (10% v/v and water,2-bottle choice) daily at the onset of the dark cycle. The rats weremaintained on a reverse cycle to facilitate experimenter interactions.The animals were initially assigned to four groups equated for alcoholintakes: Group 1-vehicle (n=8); Group 2-positive control (e.g. 5.6 mg/kgAM251; n=8); Group 3-low dose test compound (n=8); and Group 4-high doseof test compound (n=8). Test compounds were generally mixed into avehicle of 30% (w/v) β-cyclodextrin in distilled water at a volume of1-2 ml/kg. Vehicle injections were given to all groups for the first twodays of the experiment. This was followed by 2 days of drug injections(to the appropriate groups) and a final day of vehicle injections. Onthe drug injection days, drugs were given sc 30 minutes prior to a2-hour alcohol access period. Alcohol intake for all animals wasmeasured during the test period and a comparison was made between drugand vehicle-treated animals to determine effects of the compounds onalcohol drinking behavior.

Additional drinking studies were done utilizing female C57BI/6 mice(Charles River). Several studies have shown that this strain of micewill readily consume alcohol with little to no manipulation required(Middaugh et al., “Ethanol Consumption by C57BL/6 Mice: Influence ofGender and Procedural Variables” Alcohol, 17 (3), 175-183, 1999; Le etal., “Alcohol Consumption by C57BL/6, BALA/c, and DBA/2 Mice in aLimited Access Paradigm” Pharmacology Biochemisrty and Behavior, 47,375-378, 1994).

For our purposes, upon arrival (17-19 g) mice were individually housedand given unlimited access to powdered rat chow, water and a 10% (w/v)alcohol solution. After 2-3 weeks of unlimited access, water wasrestricted for 20 hours and alcohol was restricted to only 2 hoursaccess daily. This was done in a manner that the access period was thelast 2 hours of the dark part of the light cycle.

Once drinking behavior stabilized, testing commenced. Mice wereconsidered stable when the average alcohol consumption for 3 days was±20% of the average for all 3 days. Day 1 of test consisted of all micereceiving vehicle injection (sc or ip). Thirty to 120 minutes postinjection access was given to alcohol and water. Alcohol consumption forthat day was calculated (g/kg) and groups were assigned (n=7-10) so thatall groups had equivocal alcohol intake. On day 2 and 3, mice wereinjected with vehicle or drug and the same protocol as the previous daywas followed. Day 4 was wash out and no injections were given. Data wasanalyzed using repeated measures ANOVA. Change in water or alcoholconsumption was compared back to vehicle for each day of the test.Positive results would be interpreted as a compound that was able tosignificantly reduce alcohol consumption while having no effect on water

Oxygen Consumption

Methods:

Whole body oxygen consumption is measured using an indirect calorimeter(Oxymax from Columbus Instruments, Columbus, Ohio.) in male SpragueDawley rats (if another rat strain or female rats are used, it will bespecified). Rats (300-380 g body weight) are placed in the calorimeterchambers and the chambers are placed in activity monitors. These studiesare done during the light cycle. Prior to the measurement of oxygenconsumption, the rats are fed standard chow ad libitum. During themeasurement of oxygen consumption, food is not available. Basal pre-doseoxygen consumption and ambulatory activity are measured every 10 minutesfor 2.5 to 3 hours. At the end of the basal pre-dosing period, thechambers are opened and the animals are administered a single dose ofcompound (the usual dose range is 0.001 to 10 mg/kg) by oral gavage (orother route of administration as specified, i.e. s.c., i.p., i.v.).Drugs are prepared in methylcellulose, water or other specified vehicle(examples include PEG400, 30% beta-cyclo dextran and propylene glycol).Oxygen consumption and ambulatory activity are measured every 10 minutesfor an additional 1-6 hours post-dosing.

The Oxymax calorimeter software calculates the oxygen consumption(ml/kg/h) based on the flow rate of air through the chambers anddifference in oxygen content at inlet and output ports. The activitymonitors have 15 infrared light beams spaced one inch apart on eachaxis, ambulatory activity is recorded when two consecutive beams arebroken and the results are recorded as counts.

Resting oxygen consumption, during pre- and post-dosing, is calculatedby averaging the 10-min O₂ consumption values, excluding periods of highambulatory activity (ambulatory activity count>100) and excluding thefirst 5 values of the pre-dose period and the first value from thepost-dose period. Change in oxygen consumption is reported as percentand is calculated by dividing the post-dosing resting oxygen consumptionby the pre-dose oxygen consumption *100. Experiments will typically bedone with n=4-6 rats and results reported are mean+/− SEM.

Interpretation:

An increase in oxygen consumption of >10% is considered a positiveresult. Historically, vehicle-treated rats have no change in oxygenconsumption from pre-dose basal.

1. A compound of Formula (I) or (II)

wherein A is nitrogen and B is carbon, R⁰ is an aryl optionallysubstituted with one or more substituents or a heteroaryl optionallysubstituted with one or more substituents; R¹ is aryl optionallysubstituted with one or more substituents, heteroaryl optionallysubstituted with one or more substituents, —CH═CH—R^(1a), where R^(1a)is hydrogen or a chemical moiety selected from (C₁-C₈)alkyl, 3- to8-membered partially or fully saturated carbocyclic ring(s), 3- to8-membered partially or fully saturated heterocycle, aryl, heteroaryl,where the chemical moiety is optionally substituted with one or moresubstituents; X is a bond; R^(3a) and R^(3b) are each independentlyhydrogen, (C₁-C₄)alkyl, or halo-substituted (C₁-C₄)alkyl; and R⁴ is achemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, heteroaryl, aryl(C₁-C₄)alkyl, a 3- to 8-membered partially orfully saturated carbocyclic ring(s), heteroaryl(C₁-C₃)alkyl, 5-6membered lactone, 5- to 6-membered lactam, and a 3- to 8-memberedpartially or fully saturated heterocycle, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof, a prodrug of said compound or said salt, or asolvate or hydrate of said compound, said salt or said prodrug.
 2. Thecompound of claim 1 wherein R⁴ is a chemical moiety selected from thegroup consisting of (C₁-C₈)alkyl, aryl(C₁-C₄)alkyl, 3- to 8-memberedpartially or fully saturated carbocyclic ring(s), and 3- to 8-memberedpartially or fully saturated heterocycle, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 3. The compound of claim 2 wherein R⁴ is (C₁-C₈)alkyl,halo-substituted (C₁-C₈)alkyl, cyclopentyl, cyclohexyl, piperidin-1-yl,pyrrolidin-1-yl, or morpholin-1-yl; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 4. Thecompound of claim 1, 2 or 3 wherein said compound is a compound ofFormula (I); a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 5. The compound of claim 1wherein R⁰ and R¹ are each independently a phenyl substituted with 1 to3 substituents independently selected from the group consisting of halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 6. The compound of claim 5 wherein R⁰ and R¹are each independently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 7. The compound of claim 6wherein R⁰ is 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4-difluorophenyl;and R¹ is 4-chlorophenyl, 4-cyanophenyl, or 4-fluorophenyl; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 8. The compound of claim 4 selected from thegroup consisting of2-(2-chloro-phenyl)-5-isopropyl-3-(3,4,5-trifluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2,3-bis-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-5-isopropyl-3-(4-methoxymethyl-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-(2-fluoro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-5-isopropyl-3-(6-methoxy-pyridin-3-yl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(3-chloro-4-fluoro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-(4-fluoro-3-methyl-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4-methyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;4-benzyl-3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;5-tert-butyl-3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-cyclobutyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-cyclopentyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-cyclohexyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;5-tert-butyl-3-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-chloro-phenyl)-5-cyclopentyl-2-(2,4-dichloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(2-chloro-phenyl)-2-(4-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(2-chloro-phenyl)-2-(4-chloro-phenyl)-5-cyclopentyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(2-chloro-phenyl)-2-(4-chloro-phenyl)-5-cyclohexyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;5-bicyclo[2.2.1]hept-2-yl-3-(2-chloro-phenyl)-2-(4-chloro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(4-chloro-phenyl)-5-cyclopentyl-3-(2-fluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(4-chloro-phenyl)-5-cyclohexyl-3-(2-fluoro-phenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;and4-[2-(2-Chloro-phenyl)-5-isopropyl-6-oxo-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzonitrile;or a solvate or hydrate of said compound.
 9. The compound of claim 8selected from the group consisting of3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-5-(2,2,2-trifluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;and4-[2-(2-Chloro-phenyl)-5-isopropyl-6-oxo-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzonitrile;or a solvate or hydrate of said compound.
 10. The compound of claim 4wherein R¹ is —CH═CH—R^(1a), where R^(1a) is hydrogen or a chemicalmoiety selected from (C₁-C₈)alkyl, 3- to 8-membered partially or fullysaturated carbocyclic ring(s), 3- to 6-membered partially or fullysaturated heterocycle, aryl, heteroaryl, where the chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 11. The compound of claim 10 selected from the groupconsisting of2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-5-isopropyl-3-vinyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-(2,2,2-trifluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-(2,2-difluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;and2-(2-chloro-phenyl)-3-[2-(4-chloro-phenyl)-vinyl]-5-(2-fluoro-ethyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one;or a solvate or hydrate of said compound.
 12. The compound of claim 1, 2or 3 wherein said compound is a compound of Formula (II); apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 13. The compound of claim 12 wherein R⁰ andR¹ are each independently a phenyl substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 14. The compound of claim 13 wherein R⁰ andR¹ are each independently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 15. The compound of claim 14wherein R⁰ is 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4-difluorophenyl;and R¹ is 4-chlorophenyl, 4-cyanophenyl, or 4-fluorophenyl; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 16. The compound of claim 12 selected fromthe group consisting of2-(4-chloro-phenyl)-5-cyclohexyl-3-(2-fluoro-phenyl)-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole;3-(4-chloro-phenyl)-5-cyclopentyl-2-(2,4-dichloro-phenyl)-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole;and3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazole;or a solvate or hydrate of said compound.
 17. A compound of Formula(III) or (IV)

wherein A is nitrogen and B is carbon; R^(0a), R^(0b), R^(1a), andR^(1b) are each independently halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, or cyano; n and m are each independently0, 1 or 2; X is a bond; R^(3a) and R^(3b) are each independentlyhydrogen, (C₁-C₄)alkyl, or halo-substituted (C₁-C₄)alkyl; and R⁴ is achemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, heteroaryl, aryl(C₁-C₄)alkyl, a 3- to 8-membered partially orfully saturated carbocyclic ring(s), heteroaryl(C₁-C₃)alkyl, 5-6membered lactone, 5- to 6-membered lactam, and a 3- to 8-memberedpartially or fully saturated heterocycle, where said chemical moiety isoptionally substituted with one or more substituents, a pharmaceuticallyacceptable salt thereof, a solvate or hydrate of said compound or saidsalt.
 18. The compound of claim 17 wherein said compound is a compoundof Formula (III); a pharmaceutically acceptable salt thereof, a solvateor hydrate of said compound or said salt.
 19. The compound of claim 17wherein said compound is a compound of Formula (IV); a pharmaceuticallyacceptable salt thereof, a solvate or hydrate of said compound or saidsalt.
 20. A pharmaceutical composition comprising (1) a compound ofclaim 1, or a solvate or hydrate of said compound or said salt; and (2)a pharmaceutically acceptable excipient, diluent, or carrier.
 21. Thecomposition of claim 20 further comprising at least one additionalpharmaceutical agent.
 22. The composition of claim 21 wherein saidadditional pharmaceutical agent is a nicotine receptor partial agonist,an opioid antagonist, a dopaminergic agent, an attention deficitdisorder agent, or an anti-obesity agent.
 23. The composition of claim22 wherein said anti-obesity agent is selected from the group consistingof an apo-B/MTP inhibitor, a 11β-hydroxy steroid dehydrogenase-1inhibitor, peptide YY₃₋₃₆ or an analog thereof, a MCR-4 agonist, a CCK-Aagonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β₃adrenergic receptor agonist, a dopamine agonist, amelanocyte-stimulating hormone receptor analog, a 5-HT2c receptoragonist, a melanin concentrating hormone antagonist, leptin, a leptinanalog, a leptin receptor agonist, a galanin antagonist, a lipaseinhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, athyromimetic agent, dehydroepiandrosterone or analog thereof, aglucocorticoid receptor antagonist, an orexin receptor antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,a human agouti-related protein antagonist, a ghrelin receptorantagonist, a histamine 3 receptor antagonist or inverse agonist, and aneuromedin U receptor agonist.